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Chidambaram K, Rekha A, Goyal A, Rana M. Targeting KRAS-G12C in lung cancer: The emerging role of PROTACs in overcoming resistance. Pathol Res Pract 2025; 270:155954. [PMID: 40233529 DOI: 10.1016/j.prp.2025.155954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/17/2025]
Abstract
In lung cancer, KRAS mutations, especially the G12C, favor aggressive tumor growth and resistance to standard therapies. Although first-generation inhibitors of KRAS G12C, such as sotorasib and adagrasib, are highly effective in early-phase studies, resistance invariably develops under selective inhibition pressure and rarely leads to sustained long-term treatment benefits. As a novel approach to targeting KRAS mutations in lung cancer, PROTAC (Proteolysis Targeting Chimera) technology is explored in this review. The PROTACs take advantage of the cell's ubiquitin-proteasome system to selectively degrade KRAS proteins, overcoming the dilemma of a lack of traditional binding sites and the means of resistance. We review recent progress with KRAS-specific PROTACs and their mechanisms, clinical application, and effectiveness at targeting primary KRAS oncogenes and secondary drivers and signaling pathways contributing to therapeutic resistance. Also, the synergies between PROTACs and immunotherapies or chemotherapies are further amplified. This review also underscores PROTAC technology's promise to advance precision medicine by providing durable treatment options for KRAS-driven lung cancers. It addresses future directions for optimizing PROTAC efficacy, bioavailability, and patient-specific applications.
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Affiliation(s)
- Kumarappan Chidambaram
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.
| | - A Rekha
- Dr DY Patil Medical college , Hospital and Research Centre, Pimpri , Pune, India
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, UP 281406, India
| | - Mohit Rana
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
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2
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Ye W, An D, Ou WB. SMARCA4: Promises and challenges in the treatment of cancers. Cancer Lett 2025; 625:217811. [PMID: 40398707 DOI: 10.1016/j.canlet.2025.217811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 05/09/2025] [Accepted: 05/18/2025] [Indexed: 05/23/2025]
Abstract
The SWI/SNF (switch/sucrose non-fermentable) related BAF (BRG1/BRM-related factor) chromatin remodeling complex subunit ATPase 4 (SMARCA4) is a gene with a high mutation frequency in the SWI/SNF complex. It plays a role as an ATP-dependent catalytic subunit, participates in remodeling chromatin structure and regulation of gene expression, and is closely related to the poor prognosis of malignant tumors. It is imperative to conduct a comprehensive investigation into the distinctive biological functions and mechanisms by which SMARCA4 contributes to cancer development and to devise targeted therapeutic strategies. Despite numerous studies associating SMARCA4 with the regulation of essential genes, ferroptosis, autophagy, lipid metabolism, and oxidative stress, the precise mechanisms of SMARCA4 in tumors remain unclear. Patients with SMARCA4 mutations exhibit a poor prognosis and demonstrate limited responsiveness to surgery, targeted therapies, immunotherapy, and chemotherapies. Thus, SMARCA4 emerges as a promising biomarker and therapeutic target. However, the development of more effective precision therapy tools remains an urgent unmet need. The unique molecular characteristics of SMARCA4 pose significant challenges for targeted drug development. Notably, the discovery of inhibitors targeting SMARCA4 synthetic lethal partners and associated pathways has marked a breakthrough in this field. Monotherapies directed against SMARCA4 face several limitations, including drug resistance, suboptimal objective response rates, and dose-limiting toxicities. Consequently, the exploration of combinatorial therapeutic strategies for SMARCA4 deficiency populations represents a critical direction for future clinical translation.
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Affiliation(s)
- Wei Ye
- Department of Biopharmaceutics, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China
| | - Ding An
- Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China
| | - Wen-Bin Ou
- Department of Biopharmaceutics, Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China; Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang, China.
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Pan Y, Yan L, Wang S, Li H, Chen Q. Case Report: Ensartinib as a first-line treatment for SMARCA4-deficient and EML4-ALK non-small cell lung cancer. Front Oncol 2025; 15:1530142. [PMID: 40416876 PMCID: PMC12098044 DOI: 10.3389/fonc.2025.1530142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 04/14/2025] [Indexed: 05/27/2025] Open
Abstract
SMARC4 is the catalytic subunit of the SWI/SNF chromatin remodeling complex and is one of the most common altered chromatin remodeling ATPases in cancer. Studies have indicated that SMARCA4 loss is associated with highly aggressive tumors, independently predicting shorter overall and disease-specific survival. SMARCA4-deficient non-small cell lung cancer (NSCLC) primarily affects male individuals, especially smokers, and is characterized by large, aggressive tumors. Cases of SMARCA4 deletion combined with actionable driver gene mutations (e.g., ALK) are rarely reported. In this report, we describe a male non-smoker diagnosed with SMARCA4-deficient, EML4-ALK non-small cell lung cancer who has been undergoing ensartinib targeted therapy for 3 months, resulting in a significant partial response. We also propose that, from a signaling perspective, the presence of SMARCA4 deficiency may influence the sensitivity of EML4-ALK NSCLC to targeted therapy, highlighting the need for further investigation into the underlying mechanisms and the exploration of novel therapeutic approaches.
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Affiliation(s)
- Yanqing Pan
- Department of Respiratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Lingxin Yan
- Department of Respiratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shaoxi Wang
- Department of Respiratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Huiling Li
- Department of Respiratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Quanfang Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Zou X, Zhou X, Guo X, Pan L, Li W. SMARCA4 deficiency: implications for non-small cell lung cancer and management strategies, with relevance to and distinctions from thoracic undifferentiated tumor. Transl Lung Cancer Res 2025; 14:1456-1470. [PMID: 40386720 PMCID: PMC12082232 DOI: 10.21037/tlcr-24-927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 02/19/2025] [Indexed: 05/20/2025]
Abstract
In 2021, the fifth edition of the World Health Organization (WHO) classification of thoracic tumors introduced a new category, "Thoracic SMARCA4-deficient undifferentiated tumor", highlighting SMARCA4 deficiency as a key molecular marker for classifying as "other pulmonary epithelial tumors". SMARCA4 is a gene encoding a protein involved in chromatin remodeling, and approximately 8% of non-small cell lung cancer (NSCLC) patients exhibit SMARCA4 deletions. These patients are more prone to drug resistance, early recurrence, and unfavorable clinical outcomes. Moreover, NSCLC patients with concomitant SMARCA4 mutations may not benefit from currently available treatments, underscoring the distinctiveness of this subgroup. Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent distinct entities from SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). This distinction is supported by their divergent pathological characteristics, demographic profiles, and survival outcomes. NSCLC cases deficient in SMARCA4 exhibit high malignancy, yet the precise biological mechanisms underlying this phenomenon remain under intensive investigation. Pathological examination and immunohistochemistry can effectively differentiate SMARCA4-UT from SMARCA4-dNSCLC. SMARCA4-UT typically manifests as adenocarcinoma or, more rarely, as squamous cell carcinoma with undifferentiated rhabdomyoblastic morphology. Therefore, elucidating the mechanisms underlying SMARCA4 alterations in NSCLC and their regulatory roles in tumorigenesis and the microenvironment is crucial. This article aims to discuss the structure, biological functions, significance in NSCLC development, and emerging potential therapeutic strategies related to SMARCA4 while providing clinical practice guidance for NSCLC patients with SMARCA4 deletions.
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Affiliation(s)
- Xin Zou
- Department of Respiratory and Critical Care Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, China
- Institute for Lung Disease, Air Force Medical University, Xi’an, China
| | - Xiaoqing Zhou
- Department of Disease Control and Prevention, Xi’an Eighth Hospital, Xi’an, China
| | - Xian Guo
- Department of Respiratory and Critical Care Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, China
- Institute for Lung Disease, Air Force Medical University, Xi’an, China
| | - Lei Pan
- Department of Respiratory and Critical Care Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, China
- Institute for Lung Disease, Air Force Medical University, Xi’an, China
| | - Wangping Li
- Department of Respiratory and Critical Care Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, China
- Institute for Lung Disease, Air Force Medical University, Xi’an, China
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Ghazali N, Garassino MC, Leighl NB, Bestvina CM. Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions. Ther Adv Med Oncol 2025; 17:17588359251323985. [PMID: 40093982 PMCID: PMC11907553 DOI: 10.1177/17588359251323985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/05/2025] [Indexed: 03/19/2025] Open
Abstract
Kirsten rat sarcoma (KRAS) mutations are present in up to 25% of non-small-cell lung cancer (NSCLC). KRAS G12C is the most common type of mutation, representing approximately half of the cases in KRAS-mutant NSCLC. Mutations in KRAS activate the RAF-MEK-ERK pathway, leading to increased cell proliferation and survival. Recent advances in drug development have led to the approval of KRAS G12C inhibitors sotorasib and adagrasib. This review explores the emerging therapeutic strategies in KRAS G12C-mutant NSCLC, including dual checkpoint blockade and combinations with checkpoint inhibitors, with a focus on the setting of advanced disease.
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Affiliation(s)
- Nadia Ghazali
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | | | - Natasha B Leighl
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christine M Bestvina
- Department of Medicine, The University of Chicago Medicine, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA
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Xu L, Xu X, Wu P, Ye W, Zhao J, Yang J, Yao Y, Chen M, Wang X, Wang A, Fan Y. Clinical characteristics and prognostic analysis of patients with SMARCA4-deficient lung cancer. Technol Health Care 2025; 33:1014-1020. [PMID: 40105165 DOI: 10.1177/09287329241296242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
BackgroundSMARCA4-deficient NSCLC is a rare type of tumor, accounting for approximately 10% of all NSCLC. It exhibits a weak response to conventional chemotherapy and has a poor prognosis, and lacks alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes Therefore, the mechanisms of SMARCA4 in NSCLC development urgently need to be explored to identify novel biomarkers and precise therapeutic strategies for this subtype.ObjectiveThe aim of this study was to understand the clinical characteristics of this special type of tumor and its response to different treatments.MethodsWe collected clinical data from 42 patients with SMARCA4-deficient NSCLC from July 2022 to January 2024, and analyzed their clinical features and survival state.ResultsThe study included a total of 42 patients diagnosed with NSCLC and harboring SMARCA4 mutation. The majority of these patients were male with a median age of 67 years. Most patients presented at stage IV upon diagnosis with highly aggressive tumors characterized by high Ki-67 proliferation index values resulting in poor overall prognosis. Genetic testing revealed TP53 gene mutations to be most prevalent (21%), followed by KRAS mutations (13%). Patients receiving immunotherapy exhibited significantly longer median overall survival compared to those treated solely with chemotherapy. Targeted drug therapy demonstrated favorable effects in some patients.ConclusionNSCLC patients harboring SMARCA4 deficiency exhibit poor overall survival rates with a median overall survival time of 5.4 months. Immunotherapy may provide benefits for NSCLC patients with SMARCA4 deficiency.
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Affiliation(s)
- Lingling Xu
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Xianquan Xu
- Thoracic Surgery, Anhui Chest Hospital, Hefei, China
| | - Pengfei Wu
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Wei Ye
- Pathology Department, Anhui Chest Hospital, Hefei, China
| | - Jieting Zhao
- Pathology Department, Anhui Chest Hospital, Hefei, China
| | - Jingwen Yang
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Yuanyuan Yao
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Maoxi Chen
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Xiaoyan Wang
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Anbang Wang
- Department of Oncology, Anhui Chest Hospital, Hefei, China
| | - Yanbo Fan
- Department of Oncology, Anhui Chest Hospital, Hefei, China
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Hofman P, Christopoulos P, D'Haene N, Gosney J, Normanno N, Schuuring E, Tsao MS, Quinn C, Russell J, Keating KE, López-Ríos F. Proposal of real-world solutions for the implementation of predictive biomarker testing in patients with operable non-small cell lung cancer. Lung Cancer 2025; 201:108107. [PMID: 39904223 DOI: 10.1016/j.lungcan.2025.108107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/13/2025] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
The implementation of biomarker testing for targeted therapies and immune checkpoint inhibitors is a cornerstone in the management of metastatic and locally advanced non-small cell lung cancer (NSCLC), playing a pivotal role in guiding treatment decisions and patient care. The emergence of precision medicine in the realm of operable NSCLC has been marked by the recent approvals of osimertinib, atezolizumab, nivolumab, pembrolizumab and alectinib for early-stage disease, signifying a shift towards more tailored therapeutic strategies. Concurrently, the landscape of this disease is rapidly evolving, with several further pending approvals and numerous clinical trials in progress. To harness the benefits of these innovative neo-adjuvant and adjuvant therapies, the integration of predictive biomarker testing into standard clinical protocols is imperative for patients with operable NSCLC. A multidisciplinary international consortium has identified three primary obstacles impeding the effective testing of patients with operable NSCLC. These challenges encompass the limited number of test requests by physicians, the inadequacy of tissue samples for comprehensive testing, and the prevalence of cost-reduction measures leading to suboptimal testing practices. This review delineates the aforementioned challenges and proposed solutions, and strategic recommendations aimed at enhancing the testing process. By addressing these issues, we strive to optimize patient outcomes in operable NSCLC, ensuring that individuals receive the most appropriate and effective care based on their unique disease profile.
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Affiliation(s)
- Paul Hofman
- Laboratory of Clinical and Experimental Pathology, IHU RespirERA, FHU OncoAge, IRCAN, Biobank 0033-00025, Pasteur Hospital, University Côte d'Azur, Nice, France.
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumour Diseases at Heidelberg University Hospital, Heidelberg, Germany
| | - Nicky D'Haene
- Department of Pathology, Hopital Universitaire de Bruxelles (H.U.B.), Université Libre de Bruxelles, Brussels, Belgium
| | - John Gosney
- Cellular Pathology, Royal Liverpool and Broadgreen Hospitals NHS Trust, Liverpool, UK
| | - Nicola Normanno
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Ed Schuuring
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ming-Sound Tsao
- Princess Margaret Cancer Center, University Health Network, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Christine Quinn
- Diaceutics PLC, Dataworks at Kings Hall Health and Wellbeing Park, Belfast, UK
| | - Jayne Russell
- Diaceutics PLC, Dataworks at Kings Hall Health and Wellbeing Park, Belfast, UK
| | - Katherine E Keating
- Diaceutics PLC, Dataworks at Kings Hall Health and Wellbeing Park, Belfast, UK
| | - Fernando López-Ríos
- Department of Pathology, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Research Institute Hospital Universitario 12 de Octubre (i+12). CIBERONC, Madrid, Spain
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Sharie AHA, Jadallah RK, Al-Bataineh MZ, Obeidat LE, Lataifeh H, Tarad MI, Khasawneh MQ, Almdallal W, El-Elimat T, Alali FQ. Lung Adenocarcinoma With Bone Metastases: Clinicogenomic Profiling and Insights Into Prognostic Factors. Cancer Control 2025; 32:10732748251325587. [PMID: 40128173 PMCID: PMC11938876 DOI: 10.1177/10732748251325587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 02/08/2025] [Accepted: 02/17/2025] [Indexed: 03/26/2025] Open
Abstract
IntroductionLung adenocarcinoma is the leading cause of cancer-related mortality worldwide. Understanding the clinicopathological profiles and genomic drivers of its metastatic patterns is a crucial step for risk stratification. Herein, we investigated the clinicogenomic features of bone metastases in lung adenocarcinoma and their prognostic value.MethodsA retrospective cohort study with a total of 4064 patients with various metastatic patterns of lung adenocarcinoma were included, obtaining relevant clinical data and genomic profiles. Patients were categorized based on the presence or absence of bone metastases. A comparative analysis of both groups in terms of demographics, disease status, somatic mutations, and microsatellite instability was carried out. Significantly different variables were tested for their association with bone metastases. Cox regression analyses were utilized to identify independent survival prognostic variables in the bone metastases sub-cohort.ResultsGender, concomitant metastases (to adrenal gland, nervous system, lymph nodes, liver, lung, mediastinum, pleura, and skin), and aberrations in TP53, EGFR, KEAP1, and MYC were associated with bone metastases in lung adenocarcinoma. Survival analyses within the bone metastases sub-cohort have illustrated the following variables to possess poor prognostic signature including age > 75, female gender, White ethnicity, distant metastases (adrenal gland, central nervous system, intra-abdominal, and liver), EGFR (wild type), KEAP1 (mutant), MYC (mutant), KRAS (mutant), and SMARCA4 (mutant).ConclusionKey clinical and genomic factors associated with lung adenocarcinoma bone metastases have been highlighted, providing exploratory insights into high-risk individuals. Future studies should be directed to validate these prognostic variables in larger, more diverse cohorts to enhance generalizability.
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Affiliation(s)
- Ahmed H. Al Sharie
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | | | | | | | - Hanin Lataifeh
- Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Mahmoud I. Tarad
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | | | - Walaa Almdallal
- Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Tamam El-Elimat
- Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Feras Q. Alali
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
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Zhang Y, Sun D, Han W, Yang Z, Lu Y, Zhang X, Wang Y, Zhang C, Liu N, Hou H. SMARCA4 mutations and expression in lung adenocarcinoma: prognostic significance and impact on the immunotherapy response. FEBS Open Bio 2024; 14:2086-2103. [PMID: 39322625 PMCID: PMC11609588 DOI: 10.1002/2211-5463.13899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/20/2024] [Accepted: 09/10/2024] [Indexed: 09/27/2024] Open
Abstract
The switch/sucrose non-fermenting (SWI/SNF) complex family includes important chromatin-remodeling factors that are frequently mutated in lung adenocarcinoma (LUAD). However, the role of one family member, SMARCA4, in LUAD prognosis and immunotherapy sensitivity remains unclear. In the present study, 6745 LUAD samples from the cBioPortal database were used to analyze the relationships between SMARCA4 mutations and patient prognoses and clinical characteristics. Additionally, we examined the correlation between SMARCA4 mutations and prognosis in patients treated with immunotherapy using two immune-related datasets. SMARCA4 mutations and low expression were associated with shorter survival, and mutations were associated with a high tumor mutational burden and high microsatellite instability. SMARCA4 mutations were accompanied by KRAS, KEAP1, TP53 and STK11 mutations. No significant difference was observed in the immunotherapy response between patients with and without SMARCA4 mutations. When KRAS or STK11 mutations were present, immunotherapy effectiveness was poorer; however, when both SMARCA4 and TP53 mutations were present, immunotherapy was more effective. Furthermore, low SMARCA4 expression predicted a higher immunophenoscore, and SMARCA4 expression was correlated with certain immune microenvironment features. Taken together, our results suggest that SMARCA4 mutations and low expression might be associated with poor LUAD prognosis. Additionally, immunotherapy efficacy in patients with SMARCA4 mutations depended on the co-mutant genes. Thus, SMARCA4 could be an important factor to be considered for LUAD diagnosis and treatment.
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Affiliation(s)
- Yuming Zhang
- Precision Medicine Center of OncologyThe Affiliated Hospital of Qingdao University, Qingdao UniversityChina
| | - Dantong Sun
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Weizhong Han
- Department of Respiratory MedicineThe Affiliated Hospital of Qingdao UniversityChina
| | - Zhen Yang
- Department of PathologyThe Affiliated Hospital of Qingdao University, Qingdao UniversityChina
| | - Yongzhi Lu
- Department of OncologyQingdao Municipal HospitalChina
| | - Xuchen Zhang
- Precision Medicine Center of OncologyThe Affiliated Hospital of Qingdao University, Qingdao UniversityChina
| | - Yongjie Wang
- Department of Thoracic SurgeryThe Affiliation Hospital of Qingdao UniversityChina
| | - Chuantao Zhang
- Department of OncologyThe Affiliated Hospital of Qingdao UniversityChina
| | - Ning Liu
- Department of OncologyThe Affiliated Hospital of Qingdao UniversityChina
| | - Helei Hou
- Department of OncologyThe Affiliated Hospital of Qingdao UniversityChina
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Blazanin N, Liang X, Mahmud I, Kim E, Martinez S, Tan L, Chan W, Anvar NE, Ha MJ, Qudratullah M, Minelli R, Peoples M, Lorenzi P, Hart T, Lissanu Y. Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.16.613317. [PMID: 39345502 PMCID: PMC11429714 DOI: 10.1101/2024.09.16.613317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer. Previously, we and others have identified that SMARCA4-mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). Despite initial excitements, therapeutics targeting metabolic pathways such as OXPHOS have largely been disappointing due to rapid adaptation of cancer cells to inhibition of single metabolic enzymes or pathways, suggesting novel combination strategies to overcome adaptive responses are urgently needed. Here, we performed a functional genomics screen using CRISPR-Cas9 library targeting genes with available FDA approved therapeutics and identified ROCK1/2 as a top hit that sensitizes cancer cells to OXPHOS inhibition. We validate these results by orthogonal genetic and pharmacologic approaches by demonstrating that KD025 (Belumosudil), an FDA approved ROCK inhibitor, has highly synergistic anti-cancer activity in vitro and in vivo in combination with OXPHOS inhibition. Mechanistically, we showed that this combination induced a rapid, profound energetic stress and cell cycle arrest that was in part due to ROCK inhibition-mediated suppression of the adaptive increase in glycolysis normally seen by OXPHOS inhibition. Furthermore, we applied global phosphoproteomics and kinase-motif enrichment analysis to uncover a dynamic regulatory kinome upon combination of OXPHOS and ROCK inhibition. Importantly, we found converging phosphorylation-dependent regulatory cross-talk by AMPK and ROCK kinases on key RHO GTPase signaling/ROCK-dependent substrates such as PPP1R12A, NUMA1 and PKMYT1 that are known regulators of cell cycle progression. Taken together, our study identified ROCK kinases as critical mediators of metabolic adaptation of cancer cells to OXPHOS inhibition and provides a strong rationale for pursuing ROCK inhibitors as novel combination partners to OXPHOS inhibitors in cancer treatment.
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Affiliation(s)
- Nicholas Blazanin
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
| | - Xiaobing Liang
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
| | - Iqbal Mahmud
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Eiru Kim
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Sara Martinez
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Lin Tan
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Waikin Chan
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Nazanin Esmaeili Anvar
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Min Jin Ha
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Md Qudratullah
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
| | - Rosalba Minelli
- TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Michael Peoples
- TRACTION Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - Philip Lorenzi
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Traver Hart
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center
| | - Yonathan Lissanu
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center
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11
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Manolakos P, Boccuto L, Ivankovic DS. A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer. J Pers Med 2024; 14:684. [PMID: 39063938 PMCID: PMC11278206 DOI: 10.3390/jpm14070684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/11/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
This critical review investigates the impact of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations on survival outcomes in non-small cell lung cancer (NSCLC) through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. In addition, this review explores the clinicopathologic characteristics of SMARCA4 mutations and their impact on various treatment modalities, including immune checkpoint inhibitors (ICIs) both with and without Kirsten rat sarcoma viral oncogene homolog (KRAS) co-mutations. The potential ineffectiveness of ICI treatment in NSCLC is explored through the impact of SMARCA4/KRAS co-mutations on the tumor microenvironment. Moreover, this NSCLC review consistently reported statistically worse overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT), and KRAS G12C inhibitors. Designing prospective clinical SMARCA4-mutated or SMARCA4/KRAS co-mutated NSCLC trials to evaluate targeted therapies and immunotherapy may lead to a better understanding of how to improve cancer patients' outcomes and survival rates.
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Affiliation(s)
- Peter Manolakos
- Healthcare Genetics and Genomics PhD Program, Clemson University, Clemson, SC 29634, USA; (L.B.); (D.S.I.)
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Wang Y, Meraz IM, Qudratullah M, Kotagiri S, Han Y, Xi Y, Wang J, Lissanu Y. SMARCA4 mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.18.599431. [PMID: 38948751 PMCID: PMC11212967 DOI: 10.1101/2024.06.18.599431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including SMARCA4 and ARID1A . Importantly, clinical reports indicate that SMARCA4 -mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, we show that SMARCA4 loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show that SMARCA4 loss in tumor cells led to profound downregulation of STING, IL1β and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as STING, IL1β, type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated with STING and IL1β, indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response of SMARCA4 -mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.
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Wankhede D, Grover S, Hofman P. SMARCA4 alterations in non-small cell lung cancer: a systematic review and meta-analysis. J Clin Pathol 2024; 77:457-463. [PMID: 38702192 DOI: 10.1136/jcp-2024-209394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/22/2024] [Indexed: 05/06/2024]
Abstract
AIMS A mutation in the SMARCA4 gene which encodes BRG1, a common catalytic subunit of switch/sucrose non-fermentable chromatin-remodelling complexes, plays a vital role in carcinogenesis. SMARCA4 mutations are present in approximately 10% of non-small cell lung cancers (NSCLC), making it a crucial gene in NSCLC, but with varying prognostic associations. To explore this, we conducted a systematic review and meta-analysis on the prognostic significance of SMARCA4 mutations in NSCLC. METHODS Electronic database search was performed from inception to December 2022. Study characteristics and prognostic data were extracted from each eligible study. Depending on heterogeneity, pooled HR and 95% CI were derived using the random-effects or fixed-effects models. RESULTS 8 studies (11 cohorts) enrolling 8371 patients were eligible for inclusion. Data on overall survival (OS) and progression-free survival (PFS) were available from 8 (10 cohorts) and 1 (3 cohorts) studies, respectively. Comparing SMARCA4-mutated NSCLC patients with SMARCA4-wild-type NSCLC patients, the summary HRs for OS and PFS were 1.49 (95% CI 1.18 to 1.87; I2=84%) and 3.97 (95% CI 1.32 to 11.92; I2=79%), respectively. The results from the trim-and-fill method for publication bias and sensitivity analysis were inconsistent with the primary analyses. Three studies reported NSCLC prognosis for category I and II mutations separately; category I was significantly associated with OS. CONCLUSION Our findings suggest that SMARCA4 mutation negatively affects NSCLC OS and PFS. The prognostic effects of SMARCA4-co-occurring mutations and the predictive role of SMARCA4 mutation status in immunotherapy require further exploration.
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Affiliation(s)
- Durgesh Wankhede
- German Cancer Research Center, Heidelberg, Germany
- Faculty of Medicine, Univeristy of Heidelberg, Heidelberg, Germany
| | - Sandeep Grover
- Center for Human Genetics, Universitatsklinikum Giessen und Marburg - Standort Marburg, Marburg, Germany
| | - Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, University Côte d'Azur, Nice, France
- Hospital-Integrated Biobank BB-0033-00025, Pasteur Hospital, Nice, France
- University Hospital Federation OncoAge, CHU de Nice, University Côte d'Azur, Nice, France
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Li L, He K, Zhou T, Xu Y, Pang J, Yu Q, Gao Y, Shi H, Zhu H, Li M, Yu J, Yuan S. Recurrence/prognosis estimation using a molecularly positive surgical margin-based model calls for alternative curative strategies in pIIIA/N2 NSCLC. Mol Oncol 2024; 18:1649-1664. [PMID: 38327028 PMCID: PMC11161728 DOI: 10.1002/1878-0261.13600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 12/19/2023] [Accepted: 01/24/2024] [Indexed: 02/09/2024] Open
Abstract
Stage pIIIA/N2 non-small cell lung cancer (NSCLC) is primarily treated by complete surgical resection combined with neoadjuvant/adjuvant therapies. However, up to 40% of patients experience tumor recurrence. Here, we studied 119 stage pIIIA/N2 NSCLC patients who received complete surgery plus adjuvant chemotherapy (CT) or chemoradiotherapy (CRT). The paired tumor and resection margin samples were analyzed using next-generation sequencing (NGS). Although all patients were classified as negative resection margins by histologic methods, NGS revealed that 47.1% of them had molecularly positive surgical margins. Patients who tested positive for NGS-detected residual tumors had significantly shorter disease-free survival (DFS) (P = 0.002). Additionally, metastatic lymph node ratio, erb-b2 receptor tyrosine kinase 2 (ERBB2) mutations, and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) mutations were also independently associated with DFS. We used these four features to construct a COX model that could effectively estimate recurrence risk and prognosis. Notably, mutational profiling through broad-panel NGS could more sensitively detect residual tumors than the conventional histologic methods. Adjuvant CT and adjuvant CRT exhibited no significant difference in eliminating locoregional recurrence risk for stage pIIIA/N2 NSCLC patients with molecularly positive surgical margins.
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Affiliation(s)
- Li Li
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Kewen He
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Tao Zhou
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Yang Xu
- Geneseeq Research InstituteNanjing Geneseeq Technology Inc.China
| | - Jiaohui Pang
- Geneseeq Research InstituteNanjing Geneseeq Technology Inc.China
| | - Qingxi Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Yongsheng Gao
- Department of Pathology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Hongjin Shi
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - He Zhu
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Mengke Li
- Department of Pathology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
- Research Unit of Radiation OncologyChinese Academy of Medical SciencesJinanChina
| | - Shuanghu Yuan
- Department of Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanChina
- Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
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Xu M, Zhao X, Wen T, Qu X. Unveiling the role of KRAS in tumor immune microenvironment. Biomed Pharmacother 2024; 171:116058. [PMID: 38171240 DOI: 10.1016/j.biopha.2023.116058] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/03/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a "hot" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a "colder" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.
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Affiliation(s)
- Miao Xu
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China
| | - Xing Zhao
- Department of Pediatrics, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China
| | - Ti Wen
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China.
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Zhang J, Zhao R, Xu H, Dong L, Chen X. The clinicopathological features of BRG1-deficient non-small cell lung cancer and its response to immunotherapy: A single-center retrospective study. Ann Diagn Pathol 2023; 67:152192. [PMID: 37639838 DOI: 10.1016/j.anndiagpath.2023.152192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/31/2023]
Abstract
PURPOSE BRG1-deficient NSCLCs have been more intriguing recently for its highly aggressive clinical behavior and no effective therapies. This study characterized the clinical and pathological features of BRG1-deficient NSCLCs and investigated their response to immunotherapy. METHODS Forty-seven cases with BRG1-deficient NSCLC were included. Immunohistochemical markers such as BRG1, CK7, TTF-1, NapsinA, P40, HepPar-1, Ki-67, BRM, ARID1A and ARID1B were stained. Additionally, the PD-L1 expression level, overall survival, progression-free survival and disease control rate of patients received immunotherapy were evaluated. RESULTS This study revealed that: (1) Patients with BRG1-deficient NSCLC have a male predominance (89.4 %), smoker enrichment (76.6 %) and poor prognosis (median OS: 7.0 months for advanced stage). (2) Histologically, BRG1-deficient NSCLCs presented significant morphological diversity and no lepidic pattern. Inflammatory infiltration and tumor necrosis was a prominent feature. Immunohistochemical analyses showed a distinctive uniform immunophenotype (TTF-1-/NapsinA-/CK7+) in 60.9 % (28/46) of cases and HepPar-1 positive in 46.5 % (20/43) of cases. BRM loss or significant reduction coexisted in 11.8 % (4/34) of cases. No case (0/37) showed loss of ARID1A or ARID1B. (3) Eight patients with advanced tumor stage had received immunotherapy and 4 cases achieved a sustainable clinical response with the disease control rate of 50 %. CONCLUSION BRG1-deficient NSCLC showed diverse histopathological patterns and a unique immunohistochemical phenotype. ICIs-based immunotherapy is a promising therapy needs to be investigated further for BRG1- deficient NSCLC.
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Affiliation(s)
- Jing Zhang
- Respiratory and Critical Care Medicine Department, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Runze Zhao
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haimin Xu
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Dong
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Chen
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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WANG X, TU M, JIA H, LIU H, WANG Y, WANG Y, JIANG N, LU C, ZHANG G. [Evaluation of Efficacy and Prognosis Analysis of Stage III-IV SMARCA4-deficient
Non-small Cell Lung Cancer Treated by PD-1 Immune Checkpoint Inhibitors plus
Chemotherapy and Chemotherapy]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2023; 26:659-668. [PMID: 37985152 PMCID: PMC10600746 DOI: 10.3779/j.issn.1009-3419.2023.101.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND The SMARCA4 mutation has been shown to account for at least 10% of non-small cell lung cancer (NSCLC). In the present, conventional radiotherapy and targeted therapy are difficult to improve outcomes due to the highly aggressive and refractory nature of SMARCA4-deficient NSCLC (SMARCA4-DNSCLC) and the absence of sensitive site mutations for targeted drug therapy, and chemotherapy combined with or without immunotherapy is the main treatment. Effective SMARCA4-DNSCLC therapeutic options, however, are still debatable. Our study aimed to investigate the efficacy and prognosis of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy in patients with stage III-IV SMARCA4-DNSCLC. METHODS 46 patients with stage III-IV SMARCA4-DNSCLC were divided into two groups based on their treatment regimen: the chemotherapy group and the PD-1 ICIs plus chemotherapy group, and their clinical data were retrospectively analyzed. Efficacy assessment and survival analysis were performed in both groups, and the influencing factors for prognosis were explored for patients with SMARCA4-DNSCLC. RESULTS Male smokers are more likely to develop SMARCA4-DNSCLC. There was no significant difference in the objective response rate (76.5% vs 69.0%, P=0.836) between chemotherapy and the PD-1 ICIs plus chemotherapy or the disease control rate (100.0% vs 89.7%, P=0.286). The one-year overall survival rate in the group with PD-1 ICIs plus chemotherapy was 62.7%, and that of the chemotherapy group was 46.0%. The difference in median progression-free survival (PFS) between the PD-1 ICIs plus chemotherapy group and the chemotherapy group was statistically significant (9.3 mon vs 6.1 mon, P=0.048). The results of Cox regression analysis showed that treatment regimen and smoking history were independent influencing factors of PFS in patients with stage III-IV SMARCA4-DNSCLC, and family history was an individual influencing factor of overall survival in patients with stage III-IV SMARCA4-DNSCLC. CONCLUSIONS Treatment regimen may be a prognostic factor for patients with SMARCA4-DNSCLC, and patients with PD-1 ICIs plus chemotherapy may have a better prognosis.
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Luo J, Ding B, Campisi A, Chen T, Teng H, Ji C. Molecular, clinicopathological characteristics and surgical results of resectable SMARCA4-deficient thoracic tumors. J Cancer Res Clin Oncol 2023; 149:4455-4463. [PMID: 36121510 DOI: 10.1007/s00432-022-04359-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE SMARCA4-deficient thoracic tumors are rapid aggressive malignancies, often diagnosed at an advanced and inoperable stage. The value of pulmonary resection for resectable SMARCA4-deficient thoracic tumors is largely unknown. METHODS In this observational study, we included 45 patients who received surgery for stage I-III SMARCA4-deficient tumors. We compared the molecular, clinicopathological characteristics and survival between SMARCA4-dNSCLC and SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) patients. RESULTS Thirty-four SMARCA4-dNSCLC and 11 SMARCA4-dUT patients were included in this study. Molecular profiles were available in 33 out of 45 patients. The most common mutated gene was TP53 (21, 64%), and followed by STK11 (9, 27%), KRAS (5, 15%), FGFR1 (4, 12%) and ROS1 (4, 12%). There were 3 patients that harbored ALK mutation including 1 EML4-ALK rearrangement. There were 2 patients that harbored EGFR rare site missense mutation. SMARCA4-dUT patients had significance worse TTP (HR = 4.35 95% CI 1.77-10.71, p = 0.001) and OS (HR = 4.27, 95% CI 1.12-16.35, p = 0.022) compared to SMARCA4-dNSCLC patients. SMARCA4-dUT histologic type, stage II/III, R1/2 resection and lymphovascular invasion were independent poor prognostic predictors for both TTP and OS. There were 8 patients who received immunotherapy, the objective response rate was 50%. The SMARCA4-dNSCLC patient with ALK rearrangement was treated with crizotinib as second-line therapy, and achieved stable disease for 9.7 months. CONCLUSION Patients with SMARCA4-deficient tumors have a high probability of early recurrence after surgery, except for stage I patients. Immunotherapy seems to be a valuable strategy to treat recurrence.
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Affiliation(s)
- Jizhuang Luo
- Department of Thoracic Surgery, School of Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Xuhui District, Shanghai, 200030, China
| | - Bowen Ding
- Department of Pathology, School of Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Xuhui District, Shanghai, 200030, China
| | - Alessio Campisi
- Department of Thoracic Surgery, School of Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Xuhui District, Shanghai, 200030, China
- Department of Thoracic Surgery, University and Hospital Trust-Ospedale Borgo Trento, piazzale aristide stefani 1, Verona, Italy
| | - Tangbing Chen
- Department of Thoracic Surgery, School of Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Xuhui District, Shanghai, 200030, China
| | - Haohua Teng
- Department of Pathology, School of Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Xuhui District, Shanghai, 200030, China.
| | - Chunyu Ji
- Department of Thoracic Surgery, School of Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Rd, Xuhui District, Shanghai, 200030, China.
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Boiarsky D, Lydon CA, Chambers ES, Sholl LM, Nishino M, Skoulidis F, Heymach JV, Luo J, Awad MM, Janne PA, Van Allen EM, Barbie DA, Vokes NI. Molecular markers of metastatic disease in KRAS-mutant lung adenocarcinoma. Ann Oncol 2023; 34:589-604. [PMID: 37121400 PMCID: PMC10425882 DOI: 10.1016/j.annonc.2023.04.514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/11/2023] [Accepted: 04/19/2023] [Indexed: 05/02/2023] Open
Abstract
BACKGROUND Prior studies characterized the association of molecular alterations with treatment-specific outcomes in KRAS-mutant (KRASMUT) lung adenocarcinoma (LUAD). Less is known about the prognostic role of molecular alterations and their associations with metastatic disease. PATIENTS AND METHODS We analyzed clinicogenomic data from 1817 patients with KRASMUT LUAD sequenced at the Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSKCC). Patients with metastatic (M1) and nonmetastatic (M0) disease were compared. Transcriptomic data from The Cancer Genome Atlas (TCGA) were investigated to characterize the biology of differential associations with clinical outcomes. Organ-specific metastasis was associated with overall survival (OS). RESULTS KEAP1 (DFCI: OR = 2.3, q = 0.04; MSKCC: OR = 2.2, q = 0.00027) and SMARCA4 mutations (DFCI: OR = 2.5, q = 0.06; MSKCC: OR = 2.6, q = 0.0021) were enriched in M1 versus M0 tumors. On integrative modeling, NRF2 activation was the genomic feature most associated with OS. KEAP1 mutations were enriched in M1 versus M0 tumors independent of STK11 status (KEAP1MUT/STK11WT: DFCI OR = 3.0, P = 0.0064; MSKCC OR = 2.0, P = 0.041; KEAP1MUT/STK11MUT: DFCI OR = 2.3, P = 0.0063; MSKCC OR = 2.5, P = 3.6 × 10-05); STK11 mutations without KEAP1 loss were not associated with stage (KEAP1WT/STK11MUT: DFCI OR = 0.97, P = 1.0; MSKCC OR = 1.2, P = 0.33) or outcome. KEAP1/KRAS-mutated tumors with and without STK11 mutations exhibited high functional STK11 loss. The negative effects of KEAP1 were compounded in the presence of bone (HR = 2.3, P = 4.4 × 10-14) and negated in the presence of lymph node metastasis (HR = 1.0, P = 0.91). CONCLUSIONS Mutations in KEAP1 and SMARCA4, but not STK11, were associated with metastatic disease and poor OS. Functional STK11 loss, however, may contribute to poor outcomes in KEAP1MUT tumors. Integrating molecular data with clinical and metastatic-site annotations can more accurately risk stratify patients.
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Affiliation(s)
- D Boiarsky
- Department of Medicine, Tufts Medical Center, Boston
| | - C A Lydon
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston
| | - E S Chambers
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston
| | - L M Sholl
- Center for Advanced Molecular Diagnostics, Brigham & Women's Hospital & Harvard Medical School, Boston
| | - M Nishino
- Department of Radiology, Brigham and Women's Hospital, Boston
| | - F Skoulidis
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston
| | - J V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston
| | - J Luo
- Department of Medicine, Dana-Farber Cancer Institute, Boston
| | - M M Awad
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston
| | - P A Janne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston
| | - E M Van Allen
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston; Broad Institute of Harvard & MIT, Cambridge; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston
| | - D A Barbie
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston
| | - N I Vokes
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston; Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, USA.
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Pan M, Jiang C, Zhang Z, Achacoso N, Solorzano-Pinto AV, Tse P, Chung E, Suga JM, Thomas S, Habel LA. Sex- and Co-Mutation-Dependent Prognosis in Patients with SMARCA4-Mutated Malignancies. Cancers (Basel) 2023; 15:2665. [PMID: 37345003 DOI: 10.3390/cancers15102665] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/12/2023] [Accepted: 05/03/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. METHODS This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A, STK11, and Keap1 co-mutations. RESULTS Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%), STK11 (mutSTK11, 12.8%), and Keap1 (mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, [95% CI 0.92-3.18]) with a median OS of 3.0 versus 43.3 months (p < 0.001), and among the NSCLC subgroup (HR = 14.2, [95% CI 2.76-73.4]) with a median OS of 2.75 months versus un-estimable (p = 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, [95% CI 1.04-4.29]) and mutSTK11 versus wtSTK11 (HR = 2.59, [95% CI 0.87-7.73]) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, [0.06-1.97]) and mutKRAS versus wtKRAS (HR = 0.04, [0.003-.45]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, [1.12-22.32]), mutSTK11 versus wtSTK11 (HR = 13.10, [95% CI 1.16-148.26]), and mutKeap1 versus wtKeap1 (HR = 5.06, [95% CI 0.89-26.61}) were associated with worse OS. CONCLUSION In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.
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Affiliation(s)
- Minggui Pan
- Department of Oncology and Hematology, Kaiser Permanente, Santa Clara, CA 94051, USA
- Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
- Division of Oncology, Stanford University School of Medicine, Stanford, CA 94304, USA
| | - Chen Jiang
- Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
| | - Zheyang Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, and National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361102, China
| | - Ninah Achacoso
- Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
| | | | - Pam Tse
- Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
| | - Elaine Chung
- Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
| | - Jennifer Marie Suga
- Department of Oncology and Hematology, Kaiser Permanente, Vallejo, CA 94589, USA
| | - Sachdev Thomas
- Department of Oncology and Hematology, Kaiser Permanente, Vallejo, CA 94589, USA
| | - Laurel A Habel
- Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
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21
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Deng C, Deng G, Zhu X. Case Report: Nintedanib for immune-related pneumonitis triggered by anti-PD-1 treatment in a patient with SMARCA4-mutant NSCLC: a case report. Front Pharmacol 2023; 14:1177329. [PMID: 37214462 PMCID: PMC10192877 DOI: 10.3389/fphar.2023.1177329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
SMARCA4-mutant lung cancer accounts for approximately 10% of non-small-cell lung cancers (NSCLCs), has few effective treatments, and has been associated with a poor prognosis. Our case report describes a 73-year-old man who was diagnosed with SMARCA4-mutant advanced lung adenocarcinoma. Routine driver gene mutation screening was negative, and tumor tissue immunohistochemistry analysis showed the absence of the BRG1 protein (encoded by SMARCA4). In addition to the standard chemotherapy regimens, programmed cell death protein 1 (PD-1) inhibitors were administered. After three cycles of combination therapy, the focus of the primary lung tumor shrunk evidently, but radiological interstitial abnormalities emerged in the basal and subpleural areas of the bilateral lungs. The patient's clinical condition deteriorated and he was diagnosed with immune checkpoint inhibitor (ICI)-associated pneumonia. Thus, the combination regimen was discontinued, corticosteroid therapy was administered according to guidelines, and nintedanib was added, given that interstitial abnormalities were observed on chest computed tomography (CT). Following the above treatment, the patient's condition improved, the standard chemotherapy regimen was restarted, and nintedanib treatment was maintained. The patient's clinical condition continued to improve, and follow-up CT showed significant resolution of the interstitial abnormalities and stabilization of the primary tumor lesion. In summary, we report the case of a patient with SMARCA4-mutant NSCLC, which is generally considered to be associated with a poor prognosis owing to a lack of effective treatments. The patient responded favorably to initial combination therapy with ICIs, although he subsequently developed immune-related adverse events. We also found that nintedanib, a multitargeted anti-fibrotic agent, was beneficial for the treatment of immune-related lung injury and showed potential anti-tumor effects.
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22
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Jiang J, Chen Z, Gong J, Han N, Lu H. Thoracic SMARCA4-deficient undifferentiated tumor. Discov Oncol 2023; 14:51. [PMID: 37115343 PMCID: PMC10147882 DOI: 10.1007/s12672-023-00639-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 03/20/2023] [Indexed: 04/29/2023] Open
Abstract
Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently described smoking-related malignancy. The pathogenesis of SMARCA4-UT is the mutational inactivation and loss of expression of a subunit encoding the mammalian switch/sucrose nonfermenting ATPase-dependent chromatin remodeling complex (which can be mobilized using adenosine triphosphate hydrolysis nucleosomes and regulate other cellular processes including development, differentiation, proliferation, and apoptosis), in particular SMARCA4 and SMARCA2. The dynamic activity of this complex plays an important role in regulating the activation and repression of gene expression programs. SMARCA4-UT exhibits morphological features similar to the malignant rhabdoid tumor (MRT), small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT), and INI1-deficient tumor, but SMARCA4-UT differs from SCCOHT and MRT from a genomic perspective. SMARCA4-UT mainly involves the mediastinum and lung parenchyma, and appears as a large infiltrative mass that easily compresses surrounding tissues. At present, chemotherapy is a common treatment, but its efficacy is not clear. Moreover, the inhibitor of the enhancer of zeste homolog 2 showed promising efficacy in some patients with SMARCA4-UT. This study aimed to review the clinical characteristics, diagnosis, treatment, and prognosis of SMARCA4-UT.
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Affiliation(s)
- Jiapeng Jiang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
- Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Zhixin Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
- Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Jiali Gong
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People's Republic of China
- Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Na Han
- Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China
| | - Hongyang Lu
- Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
- Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, 310022, China.
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23
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Smith MR, Wang Y, D'Agostino R, Liu Y, Ruiz J, Lycan T, Oliver G, Miller LD, Topaloglu U, Pinkney J, Abdulhaleem MN, Chan MD, Farris M, Su J, Mileham KF, Xing F. Prognostic Mutational Signatures of NSCLC Patients treated with chemotherapy, immunotherapy and chemoimmunotherapy. NPJ Precis Oncol 2023; 7:34. [PMID: 36973365 PMCID: PMC10042886 DOI: 10.1038/s41698-023-00373-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Different types of therapy are currently being used to treat non-small cell lung cancer (NSCLC) depending on the stage of tumor and the presence of potentially druggable mutations. However, few biomarkers are available to guide clinicians in selecting the most effective therapy for all patients with various genetic backgrounds. To examine whether patients' mutation profiles are associated with the response to a specific treatment, we collected comprehensive clinical characteristics and sequencing data from 524 patients with stage III and IV NSCLC treated at Atrium Health Wake Forest Baptist. Overall survival based Cox-proportional hazard regression models were applied to identify mutations that were "beneficial" (HR < 1) or "detrimental" (HR > 1) for patients treated with chemotherapy (chemo), immune checkpoint inhibitor (ICI) and chemo+ICI combination therapy (Chemo+ICI) followed by the generation of mutation composite scores (MCS) for each treatment. We also found that MCS is highly treatment specific that MCS derived from one treatment group failed to predict the response in others. Receiver operating characteristics (ROC) analyses showed a superior predictive power of MCS compared to TMB and PD-L1 status for immune therapy-treated patients. Mutation interaction analysis also identified novel co-occurring and mutually exclusive mutations in each treatment group. Our work highlights how patients' sequencing data facilitates the clinical selection of optimized treatment strategies.
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Affiliation(s)
- Margaret R Smith
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yuezhu Wang
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Ralph D'Agostino
- Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Yin Liu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Jimmy Ruiz
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Thomas Lycan
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - George Oliver
- Department of Pharmacy, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Lance D Miller
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Umit Topaloglu
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
| | - Jireh Pinkney
- Department of Biology, Winston Salem State University, Winston-Salem, NC, USA
| | - Mohammed N Abdulhaleem
- Department of Hematology and Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Michael D Chan
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Michael Farris
- Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Jing Su
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kathryn F Mileham
- Department of Solid Tumor Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
| | - Fei Xing
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
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24
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Santarpia M, Ciappina G, Spagnolo CC, Squeri A, Passalacqua MI, Aguilar A, Gonzalez-Cao M, Giovannetti E, Silvestris N, Rosell R. Targeted therapies for KRAS-mutant non-small cell lung cancer: from preclinical studies to clinical development-a narrative review. Transl Lung Cancer Res 2023; 12:346-368. [PMID: 36895930 PMCID: PMC9989806 DOI: 10.21037/tlcr-22-639] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 02/03/2023] [Indexed: 02/25/2023]
Abstract
Background and Objective Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with KRAS G12C mutation. Methods In this review, we describe KRAS and the biology of KRAS-mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation. Key Content and Findings KRAS is the most frequently mutated oncogene in human cancer. The G12C is the most common KRAS mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, KRAS G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described. Conclusions The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of KRAS G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.
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Affiliation(s)
- Mariacarmela Santarpia
- Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy
| | - Giuliana Ciappina
- Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy
| | - Calogera Claudia Spagnolo
- Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy
| | - Andrea Squeri
- Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy
| | - Maria Ilenia Passalacqua
- Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy
| | - Andrés Aguilar
- Oncology Institute Dr. Rosell, IOR, Dexeus University Hospital, Barcelona, Spain
| | - Maria Gonzalez-Cao
- Oncology Institute Dr. Rosell, IOR, Dexeus University Hospital, Barcelona, Spain
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.,Cancer Pharmacology Lab, Fondazione Pisana per La Scienza, San Giuliano, Italy
| | - Nicola Silvestris
- Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy
| | - Rafael Rosell
- Oncology Institute Dr. Rosell, IOR, Dexeus University Hospital, Barcelona, Spain.,Catalan Institute of Oncology, ICO, Badalona, Spain
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BRG1: Promoter or Suppressor of Cancer? The Outcome of BRG1's Interaction with Specific Cellular Pathways. Int J Mol Sci 2023; 24:ijms24032869. [PMID: 36769189 PMCID: PMC9917617 DOI: 10.3390/ijms24032869] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
BRG1 is one of two catalytic subunits of the SWI/SNF ATP-dependent chromatin-remodeling complex. In cancer, it has been hypothesized that BRG1 acts as a tumor suppressor. Further study has shown that, under certain circumstances, BRG1 acts as an oncogene. Targeted knockout of BRG1 has proven successful in most cancers in suppressing tumor growth and proliferation. Furthermore, BRG1 effects cancer proliferation in oncogenic KRAS mutated cancers, with varying directionality. Thus, dissecting BRG1's interaction with various cellular pathways can highlight possible intermediates that can facilitate the design of different treatment methods, including BRG1 inhibition. Autophagy and apoptosis are two important cellular responses to stress. BRG1 plays a direct role in autophagy and apoptosis and likely promotes autophagy and suppresses apoptosis, supporting unfettered cancer growth. PRMT5 inhibits transcription by interacting with ATP-dependent chromatin remodeling complexes, such as SWI/SNF. When PRMT5 associates with the SWI/SNF complex, including BRG1, it represses tumor suppressor genes. The Ras/Raf/MAPK/ERK1/2 pathway in cancers is a signal transduction pathway involved in the transcription of genes related to cancer survival. BRG1 has been shown to effect KRAS-driven cancer growth. BRG1 associates with several proteins within the signal transduction pathway. In this review, we analyze BRG1 as a promising target for cancer inhibition and possible synergy with other cancer treatments.
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SMARCA4: Current status and future perspectives in non-small-cell lung cancer. Cancer Lett 2023; 554:216022. [PMID: 36450331 DOI: 10.1016/j.canlet.2022.216022] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/07/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022]
Abstract
SMARCA4, also known as transcription activator, is an ATP-dependent catalytic subunit of SWI/SNF (SWItch/Sucrose NonFermentable) chromatin-remodeling complexes that participates in the regulation of chromatin structure and gene expression by supplying energy. As a tumor suppressor that has aberrant expression in ∼10% of non-small-cell lung cancers (NSCLCs), SMARCA4 possesses many biological functions, including regulating gene expression, differentiation and transcription. Furthermore, NSCLC patients with SMARCA4 alterations have a weak response to conventional chemotherapy and poor prognosis. Therefore, the mechanisms of SMARCA4 in NSCLC development urgently need to be explored to identify novel biomarkers and precise therapeutic strategies for this subtype. This review systematically describes the biological functions of SMARCA4 and its role in NSCLC development, metastasis, functional epigenetics and potential therapeutic approaches for NSCLCs with SMARCA4 alterations. Additionally, this paper explores the relationship and regulatory mechanisms shared by SMARCA4 and its mutually exclusive catalytic subunit SMARCA2. We aim to provide innovative treatment strategies and improve clinical outcomes for NSCLC patients with SMARCA4 alterations.
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27
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Chang G, Li W, Bai H, Duan J, Wang Z, Du X, Yu R, Wang Y, Wang M, Zhu Y, Zhang X, Li L, Wan R, Wang J. Correlations of switch/sucrose nonfermentable complex mutations with clinical outcomes in advanced non-small cell lung cancer. Thorac Cancer 2022; 13:2951-2959. [PMID: 36126963 PMCID: PMC9626335 DOI: 10.1111/1759-7714.14635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. METHODS We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort. RESULTS In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR], 0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023). CONCLUSIONS In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.
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Affiliation(s)
- Geyun Chang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Weihua Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Hua Bai
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jianchun Duan
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Zhijie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xinyang Du
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ruofei Yu
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yaxi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Minghao Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yixiang Zhu
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Xue Zhang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Li Li
- Department of Medical Records, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Rui Wan
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Zhang L, Sun T, Wu XY, Fei FM, Gao ZZ. Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma. World J Clin Cases 2022; 10:10501-10515. [PMID: 36312469 PMCID: PMC9602240 DOI: 10.12998/wjcc.v10.i29.10501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/14/2022] [Accepted: 08/30/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the mortality rate continues to rise each year. SMARCA4 expression has been associated with poor prognosis in various types of cancer; however, the specific mechanism of action of SMARCA4 in HCC needs to be fully elucidated.
AIM To explore the specific mechanism of action of SMARCA4 in HCC.
METHODS Herein, the expression level of SMARCA4 as well as its association with HCC prognosis were evaluated using transcriptome profiling and clinical data of 18 different types of cancer collected from The Cancer Genome Atlas database. Furthermore, SMARCA4-high and -low groups were identified. Thereafter, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the function of SMARCA4, followed by construction of a SMARCA4-specific competing endogenous RNA (ceRNA) network using starBase database. The role of SMARCA4 in immunotherapy and its association with immune cells were assessed using correlation analysis.
RESULTS It was observed that SMARCA4 was overexpressed and negatively correlated with prognosis in HCC. Further, SMARCA4 expression was positively associated with tumor mutational burden, microsatellite stability, and immunotherapy efficacy. The SNHG3/THUMP3-AS1-miR-139-5p-SMARCA4 ceRNA network was established and could be assumed to serve as a stimulatory mechanism in HCC.
CONCLUSION The findings of this study demonstrated that SMARCA4 plays a significant role in progression and immune infiltration in HCC. Moreover, a ceRNA network was detected, which was found to be correlated with poor prognosis in HCC. The findings of this study could contribute towards the identification of predictive markers for immunotherapy and a novel mechanism of action for HCC treatment.
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Affiliation(s)
- Lei Zhang
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Ting Sun
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Xiao-Ye Wu
- Department of Clinical Oncology, Jiaxing Second Hospital, Jiaxing 314000, Zhejiang Province, China
| | - Fa-Ming Fei
- Department of Clinical Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang Province, China
| | - Zhen-Zhen Gao
- Department of Clinical Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, Zhejiang Province, China
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Talvitie EM, Liljeroos L, Vilhonen H, Orte K, Leivo I, Kallajoki M, Taimen P. Comprehensive genomic profiling of Finnish lung adenocarcinoma cohort reveals high clinical actionability and SMARCA4 altered tumors with variable histology and poor prognosis. Neoplasia 2022; 32:100832. [PMID: 35964518 PMCID: PMC9391575 DOI: 10.1016/j.neo.2022.100832] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 10/30/2022]
Abstract
INTRODUCTION Lung adenocarcinoma is the most common type of lung cancer and typically carries a high number of mutations. However, the genetic background of the tumors varies according to patients' ethnic background and smoking status. Little data is available on the mutational landscape and the frequency of actionable genomic alterations in lung adenocarcinoma in the Finnish population. MATERIALS AND METHODS We evaluated the gene alteration frequencies of 135 stage I-IV lung adenocarcinomas operated at Turku University Hospital between 2004 and 2017 with a large commercial comprehensive genomic profiling panel. Additionally, we correlated the alterations in selected genes with disease outcomes in 115 stage I-III patients with comprehensive follow-up data. The genomic alterations in a sub-cohort of 30 never-smokers were assessed separately. RESULTS Seventy percent of patients in the overall cohort and 77% in the never-smoker sub-cohort harbored an alteration or a genomic signature targetable by FDA and/or EMA approved drug for non-small cell carcinoma, respectively. In multivariable analysis for disease-specific survival, any alteration in SMARCA4 (DSS; HR 3.911, 95%CI 1.561-9.795, P=0.004) exhibited independent prognostic significance along with stage, tumor mutation burden, and predominant histological subtypes. CONCLUSIONS Over two thirds of our overall cohort, and especially never-smokers had an actionable genomic alteration or signature. SMARCA4 alterations, detected in 7.4% of the tumors, independently predicted a shortened overall and disease-specific survival regardless of the alteration type. Most SMARCA4 alterations in our cohort were missense mutations associated with differentiated predominant histological subtypes and immunohistochemical SMARCA4/BRG1 and TTF-1 positive status.
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Affiliation(s)
- Eva-Maria Talvitie
- Department of Genomics, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland.
| | | | - Heikki Vilhonen
- University of Turku, Department of Pulmonary Diseases and Clinical Allergology and Division of Medicine, Department of Pulmonary Diseases, Turku University Hospital, Hämeentie 11, 20521 Turku, Finland
| | - Katri Orte
- Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland
| | - Ilmo Leivo
- Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland; Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
| | - Markku Kallajoki
- Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland
| | - Pekka Taimen
- Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland; Institute of Biomedicine and FICAN West Cancer Centre, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
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Zhang CW, Zhou B, Liu YC, Su LW, Meng J, Li SL, Wang XL. LINC00365 inhibited lung adenocarcinoma progression and glycolysis via sponging miR-429/KCTD12 axis. ENVIRONMENTAL TOXICOLOGY 2022; 37:1853-1866. [PMID: 35426242 DOI: 10.1002/tox.23532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 02/15/2022] [Accepted: 03/25/2022] [Indexed: 06/14/2023]
Abstract
This study researched the function of long non-coding RNA LINC00365 in lung adenocarcinoma (LAD) progression. LINC00365, miR-429, and KCTD12 expression in the LAD clinical tissues and cells were detcetd by qRT-PCR and Western blot. LINC00365, miR-429, and KCTD12 effects on H1975 cells malignant phenotype were detected by cell counting kit-8 assay, clone formation experiment, Transwell experiment, and glycolysis. Dual luciferase reporter gene assay and RNA pull-down assay were implemented. LINC00365 effect on H1975 cells in vivo growth was detected. LINC00365 was low expressed in the LAD patients and cells, associating with poor outcome. LINC00365 up-regulation attenuated H1975 cells proliferation, migration, invasion, glycolysis and in vivo growth. LINC00365 inhibited KCTD12 expression by sponging miR-429. miR-429 up-regulation and KCTD12 down-regulation partial reversed LINC00365 inhibition on H1975 cells malignant phenotype. Thus, LINC00365 inhibited LAD progression and glycolysis via targeting miR-429/KCTD12 axis. LINC00365 might be a potential candidate for LAD target treatment clinically.
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Affiliation(s)
- Cheng-Wei Zhang
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Bin Zhou
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Yan-Chao Liu
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Li-Wei Su
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Jie Meng
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Shao-Lei Li
- Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
| | - Xue-Long Wang
- Department of Thoracic Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
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Zhong C, Liang Y, Wang Q, Tan HW, Liang Y. Construction and validation of a novel prediction system for detection of overall survival in lung cancer patients. World J Clin Cases 2022; 10:5984-6000. [PMID: 35949842 PMCID: PMC9254183 DOI: 10.12998/wjcc.v10.i18.5984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/30/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Many factors have an aberrant effect on the overall survival of lung cancer (LC) patients. In recent years, remarkable progress has been made in immunotherapy, targeted treatment, and promising biomarkers. However, the available treatments and diagnostic methods are not specific for all patients.
AIM To establish a system for predicting poor survival in patients with LC.
METHODS The expression matrix and clinical information for this study were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. After the differential analysis of all screened genes, weighted gene coexpression network analysis was performed to analyze hub genes related to patient survival. A logistic regression model was used to construct the scoring system. The expression of the hub genes was verified by performing quantitative reverse transcription-polymerase chain reaction.
RESULTS A total of 5007 differentially expressed genes were selected for the Weighted Gene Co-expression Network Analysis algorithm. We found that the turquoise module showed the highest correlation with patient prognosis. The gene module with the greatest positive correlation with patient survival was located in the turquoise area. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses performed for the genes contained in the turquoise module indicated the potential roles of the selected genes in the regulation of LC development. In addition, protein–protein interaction analysis was performed to screen hub genes, which identified 100 hub genes located in the core area of the network. We then intersected the 100 hub genes with 75 key genes sorted by module members to identify real hub genes associated with prognosis. Forty-one genes were finally selected. We then used a logistic regression model to determine 11 independent risk genes, namely CCNB2, CDC20, CENPO, FOXM1, HJURP, NEK2, OIP5, PLK1, PRC1, SKA1, UBE2C and SPARC.
CONCLUSION We constructed a predictive model based on 11 independent risk genes to establish a system predicting the survival status of patients with non-small-cell lung carcinoma.
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Affiliation(s)
- Cheng Zhong
- Department of Respiratory, Fenghua District People’s Hospital, Ningbo 315000, Zhejiang Province, China
| | - Yun Liang
- Department of Hematology and Oncology, Fengdu People's Hospital, Chongqing 408200, China
| | - Qun Wang
- Department of Respiratory, Fenghua District People’s Hospital, Ningbo 315000, Zhejiang Province, China
| | - Hao-Wei Tan
- Department of Respiratory, Fenghua District People’s Hospital, Ningbo 315000, Zhejiang Province, China
| | - Yan Liang
- Department of Hematology and Oncology, Fengdu People's Hospital, Chongqing 408200, China
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SMARCA4-deficient lung carcinoma is an aggressive tumor highly infiltrated by FOXP3+ cells and neutrophils. Lung Cancer 2022; 169:13-21. [DOI: 10.1016/j.lungcan.2022.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/25/2022] [Accepted: 05/01/2022] [Indexed: 11/19/2022]
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Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner. Cancers (Basel) 2022; 14:cancers14071628. [PMID: 35406400 PMCID: PMC8996900 DOI: 10.3390/cancers14071628] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 12/16/2022] Open
Abstract
Simple Summary RAS mutation is the most frequent oncogenic alteration in human cancers and KRAS is the most frequently mutated, notably in non-small cell lung carcinomas (NSCLC). Various attempts to inhibit KRAS in the past were unsuccessful in these latter tumors. However, recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target KRAS G12C-mutated tumors, which seems promising for patient treatment and should soon be administered in daily practice for non-squamous (NS)-NSCLC. In this context, it will be mandatory to systematically assess the KRAS status in routine clinical practice, at least in advanced NS-NSCLC, leading to new challenges for thoracic oncologists. Abstract KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment.
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Shen M, Qi R, Ren J, Lv D, Yang H. Characterization With KRAS Mutant Is a Critical Determinant in Immunotherapy and Other Multiple Therapies for Non-Small Cell Lung Cancer. Front Oncol 2022; 11:780655. [PMID: 35070984 PMCID: PMC8766810 DOI: 10.3389/fonc.2021.780655] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a frequent type of cancer, which is mainly characterized clinically by high aggressiveness and high mortality. KRAS oncoprotein is the most common molecular protein detected in NSCLC, accounting for 25% of all oncogenic mutations. Constitutive activation of the KRAS oncoprotein triggers an intracellular cascade in cancer cells, leading to uncontrolled cell proliferation of cancer cells and aberrant cell survival states. The results of multiple clinical trials have shown that different KRAS mutation subtypes exhibit different sensitivities to different chemotherapy regimens. Meanwhile, anti-angiogenic drugs have shown differential efficacy for different subtypes of KRAS mutated lung cancer. It was explored to find if the specificity of the KRAS mutation subtype would affect PD-L1 expression, so immunotherapy would be of potential clinical value for the treatment of some types of KRAS mutations. It was discovered that the specificity of the KRAS mutation affected PD-L1, which opened up immunotherapy as a potential clinical treatment option. After several breakthrough studies, the preliminary test data of many early clinical trials showed that it is possible to directly inhibit KRAS G12C mutation, which has been proved to be a targeted treatment that is suitable for about 10%-12% of patients with advanced NSCLC, having a significant impact on the prolongation of their survival and the improvement of their quality of life. This article reviews the latest progress of treatments for NSCLC with KRAS mutation, in order to gain insight into the biological diversity of lung cancer cells and their potential clinical implications, thereby enabling individualized treatment for patients with KRAS-mutant NSCLC.
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Affiliation(s)
- Mo Shen
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Rongbin Qi
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
- Department of Respiratory Medicine, Enze Hospital, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
| | - Justin Ren
- Biological Sciences, Northwestern University, Evanston, Evanston, IL, United States
| | - Dongqing Lv
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
- Department of Respiratory Medicine, Enze Hospital, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
| | - Haihua Yang
- Key Laboratory of Radiation Oncology of Taizhou, Radiation Oncology Institute of Enze Medical Health Academy, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
- Department of Radiation Oncology, Enze Hospital, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
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Lupo A. Histoséminaire de pathologie oncothoracique : cas no 7. Ann Pathol 2021; 42:164-167. [DOI: 10.1016/j.annpat.2021.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 10/19/2022]
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Peng L, Li J, Wu J, Xu B, Wang Z, Giamas G, Stebbing J, Yu Z. A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers. Front Immunol 2021; 12:762598. [PMID: 34675941 PMCID: PMC8524462 DOI: 10.3389/fimmu.2021.762598] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 09/13/2021] [Indexed: 01/04/2023] Open
Abstract
Background SMARCA4, the essential ATPase subunit of SWI/SNF chromatin remodeling complex, regulates transcription through the control of chromatin structure and is increasingly thought to play significant roles in human cancers. This study aims to explore the potential role of SMARCA4 with a view to providing insights on pathologic mechanisms implicated here. Methods The potential roles of SMARCA4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. The expression difference, mutation and phosphorylation status, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), and immune cell infiltration related to SMARCA4 were analyzed. Results High expression levels of SMARCA4 were observed in most cancer types. SMARCA4 expression in tumor samples correlates with poor overall survival in several cancers. Lung adenocarcinoma cases with altered SMARCA4 showed a poorer prognosis. Enhanced phosphorylation levels of S613, S695, S699, and S1417 were observed in several tumors, including breast cancer. SMARCA4 correlated with tumor immunity and associated with different immune cells and genes in different cancer types. TMB, MSI, MMR, and DNA methylation correlated with SMARCA4 dysregulation in cancers. SMARCA4 expression was negatively associated with CD8+ T-cell infiltration in several tumors. Furthermore, the SWI/SNF superfamily-type complex and ATPase complex may be involved in the functional mechanisms of SMARCA4, albeit these data require further confirmation. Conclusions Our study offers a comprehensive understanding of the oncogenic roles of SMARCA4 across different tumors. SMARCA4 may correlate with tumor immunity.
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Affiliation(s)
- Ling Peng
- Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Jisheng Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jie Wu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bin Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiqiang Wang
- Department of Urology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang, China
| | - Georgios Giamas
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - Justin Stebbing
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Zhentao Yu
- Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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Alessi JV, Ricciuti B, Spurr LF, Gupta H, Li YY, Glass C, Nishino M, Cherniack AD, Lindsay J, Sharma B, Felt KD, Rodig SJ, Cheng ML, Sholl LM, Awad MM. SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition. J Thorac Oncol 2021; 16:1176-1187. [PMID: 33845210 DOI: 10.1016/j.jtho.2021.03.024] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/17/2021] [Accepted: 03/21/2021] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear. METHODS We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1). RESULTS Of 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77-1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64-1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38-0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36-0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs. CONCLUSIONS Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.
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Affiliation(s)
- Joao V Alessi
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Biagio Ricciuti
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Liam F Spurr
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois
| | - Hersh Gupta
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Yvonne Y Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Carolyn Glass
- Department of Pathology, Duke University Hospital, Durham, North Carolina
| | - Mizuki Nishino
- Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts; Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Andrew D Cherniack
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - James Lindsay
- Knowledge Systems Group, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Bijaya Sharma
- ImmunoProfile, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kristen D Felt
- ImmunoProfile, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Scott J Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Michael L Cheng
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients. Cells 2021; 10:cells10081920. [PMID: 34440689 PMCID: PMC8394288 DOI: 10.3390/cells10081920] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/21/2021] [Accepted: 07/26/2021] [Indexed: 11/16/2022] Open
Abstract
Lung cancers are ranked third among the cancer incidence in France in the year 2020, with adenocarcinomas being the commonest sub-type out of ~85% of non-small cell lung carcinomas. The constant evolution of molecular genotyping, which is used for the management of lung adenocarcinomas, has led to the current focus on tumor suppressor genes, specifically the loss of function mutation in the SMARCA4 gene. SMARCA4-deficient adenocarcinomas are preponderant in younger aged male smokers with a predominant solid morphology. The importance of identifying SMARCA4-deficient adenocarcinomas has gained interest for lung cancer management due to its aggressive behavior at diagnosis with vascular invasion and metastasis to the pleura seen upon presentation in most cases. These patients have poor clinical outcome with short overall survival rates, regardless of the stage of disease. The detection of SMARCA4 deficiency is possible in most pathology labs with the advent of sensitive and specific immunohistochemical antibodies. The gene mutations can be detected together with other established lung cancer molecular markers based on the current next generation sequencing panels. Sequencing will also allow the identification of associated gene mutations, notably KRAS, KEAP1, and STK11, which have an impact on the overall survival and progression-free survival of the patients. Predictive data on the treatment with anti-PD-L1 are currently uncertain in this high tumor mutational burden cancer, which warrants more groundwork. Identification of target drugs is also still in pre-clinical testing. Thus, it is paramount to identify the SMARCA4-deficient adenocarcinoma, as it carries worse repercussions on patient survival, despite having an exceptionally low prevalence. Herein, we discuss the pathophysiology of SMARCA4, the clinicopathological consequences, and different detection methods, highlighting the perspectives and challenges in the assessment of SMARCA4 deficiency for the management of non-small cell lung cancer patients. This is imperative, as the contemporary shift on identifying biomarkers associated with tumor suppressor genes such as SMARCA4 are trending; hence, awareness of pathologists and clinicians is needed for the SMARCA4-dNSCLC entity with close follow-up on new management strategies to overcome the poor possibilities of survival in such patients.
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What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy. JOURNAL OF MOLECULAR PATHOLOGY 2021. [DOI: 10.3390/jmp2020015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The discovery and clinical validation of biomarkers predictive of the response of non-squamous non-small-cell lung carcinomas (NS-NSCLC) to therapeutic strategies continue to provide new data. The evaluation of novel treatments is based on molecular analyses aimed at determining their efficacy. These tests are increasing in number, but the tissue specimens are smaller and smaller and/or can have few tumor cells. Indeed, in addition to tissue samples, complementary cytological and/or blood samples can also give access to these biomarkers. To date, it is recommended and necessary to look for the status of five genomic molecular biomarkers (EGFR, ALK, ROS1, BRAFV600, NTRK) and of a protein biomarker (PD-L1). However, the short- and more or less long-term emergence of new targeted treatments of genomic alterations on RET and MET, but also on others’ genomic alteration, notably on KRAS, HER2, NRG1, SMARCA4, and NUT, have made cellular and blood samples essential for molecular testing. The aim of this review is to present the interest in using cytological and/or liquid biopsies as complementary biological material, or as an alternative to tissue specimens, for detection at diagnosis of new predictive biomarkers of NS-NSCLC.
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Nambirajan A, Jain D. Recent updates in thoracic SMARCA4-deficient undifferentiated tumor. Semin Diagn Pathol 2021; 38:83-89. [PMID: 34147303 DOI: 10.1053/j.semdp.2021.06.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 06/01/2021] [Indexed: 12/16/2022]
Abstract
Germline inactivating mutations in SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene encoding for BRG1 (Brahma related gene-1) are the molecular drivers in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) and in malignant rhabdoid tumors (MRT) that occur in the context of rhabdoid tumor predisposition syndrome-type 2. Somatic SMARCA4 mutations and/or loss of BRG1 have been identified in a variety of adult-onset epithelial and mesenchymal neoplasms. Among thoracic tumors, these include subsets of smoking-related non-small cell lung carcinoma (NSCLC) and a relatively rare, newly recognised tumor entity: thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Less than 100 cases of SMARCA4-UT have been reported to date. They present as large compressive and infiltrative mediastinal, lung and/or pleural masses in middle-aged male smokers. They are undifferentiated tumors composed of sheets of small/epithelioid and/or rhabdoid tumor cells variably expressing epithelial markers and consistently showing loss of BRG1 and the closely related protein, Brahma (BRM). Frequent expression of stem cell markers (SOX2, CD34, SALL4) is noted. Despite gene expression profiles similar to MRTs and SCCOHT, they show striking genomic overlap with SMARCA4-mutant NSCLC with frequent TP53, STK11, KEAP1, and KRAS mutations, high tumor mutation burden (TMB), and presence of smoking related molecular signatures in tumor cells. SMARCA4-UT show uniformly poor survival and are irresponsive to conventional therapies. Immunotherapy responses are variable but promising, although PDL1 expression appears to be of poor predictive value. Drugs exploiting genetic and epigenetic mechanisms of SMARCA4 antagonism hold promise for future targeted therapies.
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Affiliation(s)
- Aruna Nambirajan
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Deepali Jain
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
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