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1
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Li N, Liu CF, Zhang W, Rao GW. A New Dawn for Targeted Cancer Therapy: Small Molecule Covalent Binding Inhibitor Targeting K-Ras (G12C). Curr Med Chem 2025; 32:647-677. [PMID: 37936461 DOI: 10.2174/0109298673258913231019113814] [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: 04/20/2023] [Revised: 09/08/2023] [Accepted: 09/15/2023] [Indexed: 11/09/2023]
Abstract
K-Ras is a frequently mutated oncogene in human malignancies, and the development of inhibitors targeting various oncogenic K-Ras mutant proteins is a major challenge in targeted cancer therapy, especially K-Ras(G12C) is the most common mutant, which occurs in pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and other highly prevalent malignancies. In recent years, significant progress has been made in developing small molecule covalent inhibitors targeting K-Ras(G12C), thanks to the production of nucleophilic cysteine by the G12C mutant, breaking the "spell" that K-Ras protein cannot be used as a drug target. With the successful launch of sotorasib and adagrasib, the development of small molecule inhibitors targeting various K-Ras mutants has continued to gain momentum. In recent years, with the popularization of highly sensitive surface plasmon resonance (SPR) technology, fragment-based drug design strategies have shown great potential in the development of small molecule inhibitors targeting K-Ras(G12C), but with the increasing number of clinically reported acquired drug resistance, addressing inhibitor resistance has gradually become the focus of this field, indirectly indicating that such small molecule inhibitors still the potential for the development of these small molecule inhibitors are also indirectly indicated. This paper traces the development of small molecule covalent inhibitors targeting K-Ras(G12C), highlighting and analyzing the structural evolution and optimization process of each series of inhibitors and the previous inhibitor design methods and strategies, as well as their common problems and general solutions, in order to provide inspiration and help to the subsequent researchers.
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Affiliation(s)
- Na Li
- College of Pharmaceutical Science, Zhejiang University of Technology and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P.R. China
| | - Chen-Fu Liu
- School of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, P.R. China
| | - Wen Zhang
- College of Pharmaceutical Science, Zhejiang University of Technology and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P.R. China
| | - Guo-Wu Rao
- College of Pharmaceutical Science, Zhejiang University of Technology and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou 310014, P.R. China
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2
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Dekker SE, Deng L. Clinical Advances and Challenges in Targeting KRAS Mutations in Non-Small Cell Lung Cancer. Cancers (Basel) 2024; 16:3885. [PMID: 39594840 PMCID: PMC11593150 DOI: 10.3390/cancers16223885] [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: 10/04/2024] [Revised: 11/11/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
KRAS mutation is one of the most common oncogenic drivers in non-small cell lung cancer. Since its discovery about four decades ago, drug development targeting KRAS has been met with countless failures. Recently, KRAS G12C, a subvariant of KRAS, became the first druggable KRAS mutation. The efficacy of the first-generation KRAS inhibitor is modest, but with scientific advancement, KRAS G12C inhibitors with higher potency are on the horizon. Additionally, novel therapeutic approaches targeting other KRAS subvariants are also being explored in clinical trials with encouraging early data. We will review the clinical advances and challenges for patients with KRAS-mutated non-small cell lung cancer, with a focus on small molecule inhibitors.
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Affiliation(s)
- Simone E. Dekker
- Division of Hematology and Oncology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA;
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
| | - Lei Deng
- Division of Hematology and Oncology, Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA;
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
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3
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Torres-Jiménez J, Espinar JB, de Cabo HB, Berjaga MZ, Esteban-Villarrubia J, Fraile JZ, Paz-Ares L. Targeting KRAS G12C in Non-Small-Cell Lung Cancer: Current Standards and Developments. Drugs 2024; 84:527-548. [PMID: 38625662 DOI: 10.1007/s40265-024-02030-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2024] [Indexed: 04/17/2024]
Abstract
Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRASG12C has revolutionized the treatment of KRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.
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Affiliation(s)
- Javier Torres-Jiménez
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.
| | - Javier Baena Espinar
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
| | - Helena Bote de Cabo
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
| | - María Zurera Berjaga
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
| | - Jorge Esteban-Villarrubia
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
| | - Jon Zugazagoitia Fraile
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Luis Paz-Ares
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
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4
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Molina-Arcas M, Downward J. Exploiting the therapeutic implications of KRAS inhibition on tumor immunity. Cancer Cell 2024; 42:338-357. [PMID: 38471457 DOI: 10.1016/j.ccell.2024.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/12/2024] [Accepted: 02/14/2024] [Indexed: 03/14/2024]
Abstract
Over the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite the initial benefit of KRAS-G12C inhibitors for patients with tumors harboring this mutation, the rapid emergence of drug resistance underscores the urgent need to synergize these inhibitors with other therapeutic approaches to improve outcomes. RAS mutant tumor cells can create an immunosuppressive tumor microenvironment (TME), suggesting an increased susceptibility to immunotherapies following RAS inhibition. This provides a rationale for combining RAS inhibitory drugs with immune checkpoint blockade (ICB). However, achieving this synergy in the clinical setting has proven challenging. Here, we explore how understanding the impact of RAS mutant tumor cells on the TME can guide innovative approaches to combining RAS inhibition with immunotherapies, review progress in both pre-clinical and clinical stages, and discuss challenges and future directions.
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Affiliation(s)
| | - Julian Downward
- Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
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Gmeiner WH. Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment. Cancers (Basel) 2024; 16:1029. [PMID: 38473386 PMCID: PMC10930828 DOI: 10.3390/cancers16051029] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/24/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer (CRC) is the second-leading cause of cancer-related mortality worldwide. CRC mortality results almost exclusively from metastatic disease (mCRC) for which systemic chemotherapy is often a preferred therapeutic option. Biomarker-based stratification of mCRC enables the use of precision therapy based on individual tumor mutational profiles. Activating mutations in the RAS/RAF/MAPK pathway downstream of EGFR signaling have, until recently, limited the use of EGFR-targeted therapies for mCRC; however, the development of anti-RAS and anti-RAF therapies together with improved strategies to limit compensatory signaling pathways is resulting in improved survival rates in several highly lethal mCRC sub-types (e.g., BRAF-mutant). The use of fluoropyrimidine (FP)-based chemotherapy regimens to treat mCRC continues to evolve contributing to improved long-term survival. Future advances in chemotherapy for mCRC will need to position development relative to the advances made in precision oncology.
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Affiliation(s)
- William H Gmeiner
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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6
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Boumelha J, Molina-Arcas M, Downward J. Facts and Hopes on RAS Inhibitors and Cancer Immunotherapy. Clin Cancer Res 2023; 29:5012-5020. [PMID: 37581538 PMCID: PMC10722141 DOI: 10.1158/1078-0432.ccr-22-3655] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/19/2023] [Accepted: 08/01/2023] [Indexed: 08/16/2023]
Abstract
Although the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers of cancer growth. However, there has been very little progress in combining immunotherapies with drugs that target oncogenic driver pathways. Some of the most important oncogenes in human cancer encode RAS family proteins, although these have proven challenging to target. Recently drugs have been approved that inhibit a specific mutant form of KRAS: G12C. These have improved the treatment of patients with lung cancer harboring this mutation, but development of acquired drug resistance after initial responses has limited the impact on overall survival. Because of the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRAS G12C inhibition can indirectly affect antitumor immunity, and does so without compromising the critical role of normal RAS proteins in immune cells. This serves as a rationale for combination with immune checkpoint blockade, which can provide additional combinatorial therapeutic benefit in some preclinical cancer models. However, in clinical trials, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, in part due to treatment toxicities. A greater understanding of how oncogenic KRAS drives immune evasion and how mutant-specific KRAS inhibition impacts the tumor microenvironment can lead to novel approaches to combining RAS inhibition with immunotherapies.
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7
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Khozooei S, Veerappan S, Toulany M. YB-1 activating cascades as potential targets in KRAS-mutated tumors. Strahlenther Onkol 2023; 199:1110-1127. [PMID: 37268766 DOI: 10.1007/s00066-023-02092-8] [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: 03/02/2023] [Accepted: 04/23/2023] [Indexed: 06/04/2023]
Abstract
Y‑box binding protein‑1 (YB-1) is a multifunctional protein that is highly expressed in human solid tumors of various entities. Several cellular processes, e.g. cell cycle progression, cancer stemness and DNA damage signaling that are involved in the response to chemoradiotherapy (CRT) are tightly governed by YB‑1. KRAS gene with about 30% mutations in all cancers, is considered the most commonly mutated oncogene in human cancers. Accumulating evidence indicates that oncogenic KRAS mediates CRT resistance. AKT and p90 ribosomal S6 kinase are downstream of KRAS and are the major kinases that stimulate YB‑1 phosphorylation. Thus, there is a close link between the KRAS mutation status and YB‑1 activity. In this review paper, we highlight the importance of the KRAS/YB‑1 cascade in the response of KRAS-mutated solid tumors to CRT. Likewise, the opportunities to interfere with this pathway to improve CRT outcome are discussed in light of the current literature.
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Affiliation(s)
- Shayan Khozooei
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany
| | - Soundaram Veerappan
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany
| | - Mahmoud Toulany
- Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany.
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8
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Durojaye OA, Ejaz U, Uzoeto HO, Fadahunsi AA, Opabunmi AO, Ekpo DE, Sedzro DM, Idris MO. CSC01 shows promise as a potential inhibitor of the oncogenic G13D mutant of KRAS: an in silico approach. Amino Acids 2023; 55:1745-1764. [PMID: 37500789 DOI: 10.1007/s00726-023-03304-2] [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: 01/03/2023] [Accepted: 07/11/2023] [Indexed: 07/29/2023]
Abstract
About 30% of malignant tumors include KRAS mutations, which are frequently required for the development and maintenance of malignancies. KRAS is now a top-priority cancer target as a result. After years of research, it is now understood that the oncogenic KRAS-G12C can be targeted. However, many other forms, such as the G13D mutant, are yet to be addressed. Here, we used a receptor-based pharmacophore modeling technique to generate potential inhibitors of the KRAS-G13D oncogenic mutant. Using a comprehensive virtual screening workflow model, top hits were selected, out of which CSC01 was identified as a promising inhibitor of the oncogenic KRAS mutant (G13D). The stability of CSC01 upon binding the switch II pocket was evaluated through an exhaustive molecular dynamics simulation study. The several post-simulation analyses conducted suggest that CSC01 formed a stable complex with KRAS-G13D. CSC01, through a dynamic protein-ligand interaction profiling analysis, was also shown to maintain strong interactions with the mutated aspartic acid residue throughout the simulation. Although binding free energy analysis through the umbrella sampling approach suggested that the affinity of CSC01 with the switch II pocket of KRAS-G13D is moderate, our DFT analysis showed that the stable interaction of the compound might be facilitated by the existence of favorable molecular electrostatic potentials. Furthermore, based on ADMET predictions, CSC01 demonstrated a satisfactory drug likeness and toxicity profile, making it an exemplary candidate for consideration as a potential KRAS-G13D inhibitor.
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Affiliation(s)
- Olanrewaju Ayodeji Durojaye
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, Anhui, China.
- School of Life Sciences, University of Science and Technology of China, Hefei, 230027, Anhui, China.
- Department of Chemical Sciences, Coal City University, Emene, EnuguState, Nigeria.
| | - Umer Ejaz
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, Anhui, China
- School of Life Sciences, University of Science and Technology of China, Hefei, 230027, Anhui, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, China
| | - Henrietta Onyinye Uzoeto
- Federal College of Dental Technology, Trans-Ekulu, Enugu State, Nigeria
- Department of Biological Sciences, Coal City University, Emene, Enugu State, Nigeria
| | - Adeola Abraham Fadahunsi
- Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, 04469, USA
| | - Adebayo Oluwole Opabunmi
- RNA Medical Center, International Institutes of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, China
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Daniel Emmanuel Ekpo
- Institute of Biological Science and Technology, National Engineering Research Center for Non-Food Biorefinery, Guangxi Academy of Sciences, Nanning, 530007, China
- Department of Biochemistry, Faculty of Biological Sciences, University of Nigeria, 410001, Nsukka, Enugu State, Nigeria
| | - Divine Mensah Sedzro
- Wisconsin National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, 53715, WI, USA.
| | - Mukhtar Oluwaseun Idris
- School of Life Sciences, University of Science and Technology of China, Hefei, 230027, Anhui, China.
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9
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Wang J, Al-Majid D, Brenner JC, Smith JD. Mutant HRas Signaling and Rationale for Use of Farnesyltransferase Inhibitors in Head and Neck Squamous Cell Carcinoma. Target Oncol 2023; 18:643-655. [PMID: 37665491 DOI: 10.1007/s11523-023-00993-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2023] [Indexed: 09/05/2023]
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are often associated with poor outcomes, due at least in part to the limited number of treatment options available for those patients who develop recurrent and/or metastatic disease (R/M HNSCC). Even with the recent validation and approval of immunotherapies in the first-line setting for these patients, the need for the development of new and alternative precision medicine strategies with survival benefit is clear. Oncogenic alterations in the HRAS (Harvey rat sarcoma virus) proto-oncogene are seen in approximately 4-8% of R/M HNSCC tumors. Recently, several preclinical and clinical advancements have been made in the implementation of small-molecule inhibitors that block post-translational farnesylation of HRas, thereby abrogating its downstream oncogenic activity. In this review, we focus on the biology of wild-type and mutant HRas signaling in HNSCC, and rationale for use and outcomes of farnesyltransferase inhibitors in patients with HRAS-mutant tumors.
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Affiliation(s)
- Jiayu Wang
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Dana Al-Majid
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, MSRB III 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA
| | - J Chad Brenner
- Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA.
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, MSRB III 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA.
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Joshua D Smith
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, MSRB III 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA
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10
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Bteich F, Mohammadi M, Li T, Bhat MA, Sofianidi A, Wei N, Kuang C. Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review. Int J Mol Sci 2023; 24:12030. [PMID: 37569406 PMCID: PMC10418782 DOI: 10.3390/ijms241512030] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/21/2023] [Accepted: 07/23/2023] [Indexed: 08/13/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with a myriad of alterations at the cellular and molecular levels. Kristen rat sarcoma (KRAS) mutations occur in up to 40% of CRCs and serve as both a prognostic and predictive biomarker. Oncogenic mutations in the KRAS protein affect cellular proliferation and survival, leading to tumorigenesis through RAS/MAPK pathways. Until recently, only indirect targeting of the pathway had been investigated. There are now several KRAS allele-specific inhibitors in late-phase clinical trials, and many newer agents and targeting strategies undergoing preclinical and early-phase clinical testing. The adequate treatment of KRAS-mutated CRC will inevitably involve combination therapies due to the existence of robust adaptive resistance mechanisms in these tumors. In this article, we review the most recent understanding and findings related to targeting KRAS mutations in CRC, mechanisms of resistance to KRAS inhibitors, as well as evolving treatment strategies for KRAS-mutated CRC patients.
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Affiliation(s)
- Fernand Bteich
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA;
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.M.); (T.L.); (M.A.B.); (N.W.)
| | - Mahshid Mohammadi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.M.); (T.L.); (M.A.B.); (N.W.)
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Terence Li
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.M.); (T.L.); (M.A.B.); (N.W.)
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Muzaffer Ahmed Bhat
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.M.); (T.L.); (M.A.B.); (N.W.)
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Amalia Sofianidi
- Oncology Unit, Third Department of Internal Medicine, Sotiria General Hospital for Chest Diseases, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Ning Wei
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.M.); (T.L.); (M.A.B.); (N.W.)
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Chaoyuan Kuang
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA;
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (M.M.); (T.L.); (M.A.B.); (N.W.)
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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11
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Zaoui K, Duhamel S. RhoB as a tumor suppressor: It’s all about localization. Eur J Cell Biol 2023; 102:151313. [PMID: 36996579 DOI: 10.1016/j.ejcb.2023.151313] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/15/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
The small GTPase RhoB is distinguished from other Rho proteins by its unique subcellular localization in endosomes, multivesicular bodies, and nucleus. Despite high sequence homology with RhoA and RhoC, RhoB is mainly associated with tumor suppressive function, while RhoA and RhoC support oncogenic transformation in most malignancies. RhoB regulates the endocytic trafficking of signaling molecules and cytoskeleton remodeling, thereby controlling growth, apoptosis, stress response, immune function, and cell motility in various contexts. Some of these functions may be ascribed to RhoB's unique subcellular localization to endocytic compartments. Here we describe the pleiotropic roles of RhoB in cancer suppression in the context of its subcellular localization, and we discuss possible therapeutic avenues to pursue and highlight priorities for future research.
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12
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Liu F, Wang F, He J, Zhou S, Luo M. Correlation between KRAS mutation subtypes and prognosis in Chinese advanced non-squamous non-small cell lung cancer patients. Cancer Med 2023. [PMID: 37140194 DOI: 10.1002/cam4.5995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 04/12/2023] [Accepted: 04/17/2023] [Indexed: 05/05/2023] Open
Abstract
PURPOSE The relationship between mutant KRAS and the risk of disease progression and death in advanced non-squamous non-small cell lung cancer (NSCLC) is still controversial among current studies, and the effects of distinct KRAS mutations on prognosis may be different. This study aimed to further investigate the association between them. PATIENTS AND METHODS Of the 184 patients eventually included in the study, 108 had KRAS wild type (WT) and 76 had KRAS mutant type (MT). Kaplan-Meier curves were plotted to describe the survival for patients among groups, while log-rank tests were conducted to evaluate the survival differences. The univariate and multivariate Cox regression were performed to identify predictors, and subgroup analysis was used to verify the interaction effect. RESULTS Similar efficacy of first-line therapy was observed for KRAS MT and WT patients (p = 0.830). The association between KRAS mutation and progression-free survival (PFS) was not significant in univariate analysis (hazard ratio [HR] = 0.94; 95% CI, 0.66-1.35), and no KRAS mutation subtype significantly affected PFS. However, KRAS mutation and KRAS non-G12C were associated with increased risk of death compared to KRAS WT in univariate and multivariate analysis. Univariate and multivariate analysis also confirmed that chemotherapy combined with antiangiogenesis or immunotherapy in the KRAS mutation group was associated with decreased risk of disease progression. However, the overall survival (OS) among KRAS mutant patients received different first-line treatments did not significantly differ. CONCLUSION KRAS mutations and their subtypes are not independent negative predictors of PFS, while KRAS mutation and KRAS non-G12C were independent prognostic factors for OS. Chemotherapy combined with antiangiogenesis or immunotherapy conferred decreased risk of disease progression to KRAS mutation patients compared to single chemotherapy.
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Affiliation(s)
- Feiwen Liu
- The Third Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Zhuang Autonomous Region, China
| | - Fang Wang
- Guangxi Qianhai Life Hospital, Nanning City, Guangxi Zhuang Autonomous Region, China
| | - Jianbo He
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning City, China
| | - Shaozhang Zhou
- Department of Respiratory Oncology, Guangxi Medical University Cancer Hospital, Guangxi Zhuang Autonomous Region, Nanning City, China
| | - Min Luo
- The Third Affiliated Hospital of Guangxi Medical University, Nanning City, Guangxi Zhuang Autonomous Region, China
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13
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Ben Yahia H, Petit FM, Saada-Bouzid E. Targeting Harvey rat sarcoma viral oncogene homolog in head and neck cancer: how to move forward? Curr Opin Oncol 2023; 35:178-185. [PMID: 36966498 DOI: 10.1097/cco.0000000000000943] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2023]
Abstract
PURPOSE OF REVIEW Despite recent advances, treatment personalization remains an issue for recurrent metastatic head and neck squamous cell carcinoma (RM HNSCC) patients. After human papilloma virus (HPV) and programmed death ligand 1 (PDL1) expression, Harvey rat sarcoma viral oncogene homolog (HRAS) appears as an emerging target in this field. In this review, we summarize the features of HRAS -mutated HNSCC and its targeting by farnesyl transferase inhibitors. RECENT FINDINGS HRAS mutations define a small subgroup of RM HNSCC patients with a poor prognosis and often refractory to the standard treatments. Posttranslational processing of HRAS being dependent on farnesylation, farnesyl transferase inhibitors have been evaluated in HRAS -mutated tumors. Tipifarnib, a first in class farnesyl transferase inhibitor, has shown efficacy in phase 2 trials with HRAS -mutated tumors. Despite reported high response rates in selected population, the efficacy of Tipifarnib is inconsistent and always transient, probably because of limiting hematological toxicities leading to dose reduction and occurrence of secondary resistance mutations. SUMMARY Tipifarnib is the first in the class of farnesyl transferase inhibitors to show efficacy in HRAS -mutated RM HNSCC. The understanding of mechanisms of resistance will pave the way for the design of second-generation farnesyl transferases inhibitors.
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Affiliation(s)
- Hédi Ben Yahia
- Translational Research in Oncology Laboratory, Cote d'Azur University
- Oncopharmacology Laboratory
| | - François M Petit
- Translational Research in Oncology Laboratory, Cote d'Azur University
- Oncopharmacology Laboratory
| | - Esma Saada-Bouzid
- Translational Research in Oncology Laboratory, Cote d'Azur University
- Medical Oncology Department, Antoine Lacassagne Cancer Center, Nice, France
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14
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Karimi N, Moghaddam SJ. KRAS-Mutant Lung Cancer: Targeting Molecular and Immunologic Pathways, Therapeutic Advantages and Restrictions. Cells 2023; 12:749. [PMID: 36899885 PMCID: PMC10001046 DOI: 10.3390/cells12050749] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/02/2023] Open
Abstract
RAS mutations are among the most common oncogenic mutations in human cancers. Among RAS mutations, KRAS has the highest frequency and is present in almost 30% of non-small-cell lung cancer (NSCLC) patients. Lung cancer is the number one cause of mortality among cancers as a consequence of outrageous aggressiveness and late diagnosis. High mortality rates have been the reason behind numerous investigations and clinical trials to discover proper therapeutic agents targeting KRAS. These approaches include the following: direct KRAS targeting; synthetic lethality partner inhibitors; targeting of KRAS membrane association and associated metabolic rewiring; autophagy inhibitors; downstream inhibitors; and immunotherapies and other immune-modalities such as modulating inflammatory signaling transcription factors (e.g., STAT3). The majority of these have unfortunately encountered limited therapeutic outcomes due to multiple restrictive mechanisms including the presence of co-mutations. In this review we plan to summarize the past and most recent therapies under investigation, along with their therapeutic success rate and potential restrictions. This will provide useful information to improve the design of novel agents for treatment of this deadly disease.
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Affiliation(s)
- Nastaran Karimi
- Faculty of Medicine, Marmara University, Istanbul 34899, Turkey
| | - Seyed Javad Moghaddam
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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15
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Xu J, Xiong Y, Xu Z, Xing H, Zhou L, Zhang X. From targeted therapy to a novel way: Immunogenic cell death in lung cancer. Front Med (Lausanne) 2022; 9:1102550. [PMID: 36619616 PMCID: PMC9816397 DOI: 10.3389/fmed.2022.1102550] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer (LC) is one of the most incident malignancies and a leading cause of cancer mortality worldwide. Common tumorigenic drivers of LC mainly include genetic alterations of EGFR, ALK, KRAS, BRAF, ROS1, and MET. Small inhibitory molecules and antibodies selectively targeting these alterations or/and their downstream signaling pathways have been approved for treatment of LC. Unfortunately, following initial positive responses to these targeted therapies, a large number of patients show dismal prognosis due to the occurrence of resistance mechanisms, such as novel mutations of these genes and activation of alternative signaling pathways. Over the past decade, it has become clear that there is no possible cure for LC unless potent antitumor immune responses are induced by therapeutic intervention. Immunogenic cell death (ICD) is a newly emerged concept, a form of regulated cell death that is sufficient to activate adaptive immune responses against tumor cells. It transforms dying cancer cells into a therapeutic vaccine and stimulates long-lasting protective antitumor immunity. In this review, we discuss the key targetable genetic aberrations and the underlying mechanism of ICD in LC. Various agents inducing ICD are summarized and the possibility of harnessing ICD in LC immunotherapy is further explored.
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Affiliation(s)
- Jiawei Xu
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, China,The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Yiyi Xiong
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Zhou Xu
- The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Hongquan Xing
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, China,The Second Clinical Medical College of Nanchang University, Nanchang, China
| | - Lingyun Zhou
- International Education College, Jiangxi University of Chinese Medicine, Nanchang, China,*Correspondence: Lingyun Zhou,
| | - Xinyi Zhang
- Department of Respiratory Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, China,The Second Clinical Medical College of Nanchang University, Nanchang, China,Xinyi Zhang,
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16
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Drugging KRAS: current perspectives and state-of-art review. J Hematol Oncol 2022; 15:152. [PMID: 36284306 PMCID: PMC9597994 DOI: 10.1186/s13045-022-01375-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 10/11/2022] [Indexed: 11/10/2022] Open
Abstract
After decades of efforts, we have recently made progress into targeting KRAS mutations in several malignancies. Known as the ‘holy grail’ of targeted cancer therapies, KRAS is the most frequently mutated oncogene in human malignancies. Under normal conditions, KRAS shuttles between the GDP-bound ‘off’ state and the GTP-bound ‘on’ state. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Simultaneously, effects of KRAS mutations on tumour microenvironment were also discovered, partly owing to the universal use of immune checkpoint inhibitors. In this review, we discuss the discovery, biology, and function of KRAS in human malignancies. We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
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17
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Desilets A, Ho AL. Targeting HRAS in Head and Neck Cancer: Lessons From the Past and Future Promise. Cancer J 2022; 28:363-368. [PMID: 36165724 DOI: 10.1097/ppo.0000000000000616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT HRAS mutations define a unique biologic subset of head and neck squamous cell carcinoma. Oncogenic HRAS is uniquely dependent on posttranslational farnesylation for membrane localization and activation of downstream signaling. Tipifarnib, a farnesyltransferase inhibitor, demonstrated encouraging antitumor activity for HRAS mutant head and neck squamous cell carcinoma and modest activity for HRAS mutant salivary gland cancer. New combination strategies to circumvent intrinsic and acquired resistance to TFIs are being investigated.
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Affiliation(s)
| | - Alan L Ho
- From the Memorial Sloan Kettering Cancer Center, New York, NY
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18
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Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers. Cancers (Basel) 2022; 14:cancers14174103. [PMID: 36077640 PMCID: PMC9454753 DOI: 10.3390/cancers14174103] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/22/2022] [Accepted: 08/22/2022] [Indexed: 12/28/2022] Open
Abstract
In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.
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19
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KRAS-Mutant Non-Small-Cell Lung Cancer: From Past Efforts to Future Challenges. Int J Mol Sci 2022; 23:ijms23169391. [PMID: 36012655 PMCID: PMC9408881 DOI: 10.3390/ijms23169391] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/12/2022] Open
Abstract
KRAS is the most frequently mutated oncogene identified in human cancers. Despite the numerous efforts to develop effective specific inhibitors against KRAS, this molecule has remained "undruggable" for decades. The development of direct KRAS inhibitors, such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, was made possible with the discovery of a small pocket in the binding switch II region of KRAS G12C. However, a new challenge is represented by the necessity to overcome resistance mechanisms to KRAS inhibitors. Another area to be explored is the potential role of co-mutations in the selection of the treatment strategy, particularly in the setting of immune checkpoint inhibitors. The aim of this review was to analyze the state-of-the-art of KRAS mutations in non-small-cell lung cancer by describing the biological structure of KRAS and exploring the clinical relevance of KRAS as a prognostic and predictive biomarker. We reviewed the different treatment approaches, focusing on the novel therapeutic strategies for the treatment of KRAS-mutant lung cancers.
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20
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Kato S, Fujiwara Y, Hong DS. Targeting KRAS: Crossroads of Signaling and Immune Inhibition. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2022; 5:68-78. [PMID: 36034582 PMCID: PMC9390702 DOI: 10.36401/jipo-22-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/15/2022] [Accepted: 06/18/2022] [Indexed: 11/09/2022]
Abstract
ABSTRACT
Mutations of RAS are commonly seen in human cancers, especially in lung, colorectal, and pancreatic adenocarcinoma. Despite huge effort for decades, targeting RAS mutations has been “undruggable” because of the molecular instability of RAS protein inhibition. However, the recent discovery of the KRAS G12C inhibitor paved the way to expand therapeutic options for patients with cancer harboring the KRAS G12C mutation. At the same time, the successful development of immune checkpoint inhibitors (ICIs) drastically changed the paradigm of cancer treatment and resulted in a better understanding of the tumor immune microenvironment in patients with KRAS-mutant cancer. This review describes the following: the clinical characteristics of cancer with KRAS mutation; successful development of the KRAS G12C inhibitor and its impact on the tumor immune microenvironment; and potential new avenues such as the combination strategy using KRAS inhibitor and ICI, with preclinical and clinical rationales for overcoming resistance to inhibition of KRAS to improve therapeutic efficacy for patients with cancer harboring KRAS mutations.
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Affiliation(s)
- Shumei Kato
- 1 Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Yu Fujiwara
- 2 Department of Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY, USA
| | - David S. Hong
- 3 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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21
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Roman M, Hwang E, Sweet-Cordero EA. Synthetic Vulnerabilities in the KRAS Pathway. Cancers (Basel) 2022; 14:cancers14122837. [PMID: 35740503 PMCID: PMC9221492 DOI: 10.3390/cancers14122837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/03/2022] [Accepted: 06/05/2022] [Indexed: 02/06/2023] Open
Abstract
Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.
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22
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HRAS Q61L Mutation as a Possible Target for Non-Small Cell Lung Cancer: Case Series and Review of Literature. Curr Oncol 2022; 29:3748-3758. [PMID: 35621690 PMCID: PMC9139372 DOI: 10.3390/curroncol29050300] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction: Assessment of actionable gene mutations and oncogene fusions have made a paradigm shift in treatment strategies of non-small cell lung cancer (NSCLC). HRAS mutations involved around 0.2–0.8% of NSCLC patients, mostly on codon 61. For these patients, few data are available regarding clinical characteristics and response to therapies. Methods: Next-Generation Sequencing (NGS) done routinely at Nantes University Hospital was used to identify HRAS molecular alterations in NSCLC patients. We identified and described four HRAS p.GlnQ61Leu mutated patients. Literature of previously HRAS-mutant NSCLC cases was reviewed, and available data in solid tumour with the most advanced H-Ras specific inhibitor, tipifarnib, were presented. Results: Of 1614 patients diagnosed with advanced NSCLC from January 2018 to December 2020, four (0.25%) had HRAS p.Gln61Leu mutation. Three of them died during the first-line systemic therapy. Furthermore, three additional cases were identified in literature. All cases were current or former smokers, most of them had pleural or pericardial effusion at diagnosis. Conclusions: The clinical course of patients with HRAS-mutant NSCLC remains unclear. Furthers cases should be identified in order to clarify prognosis and response to therapies. Tipifarnib, a farnesyl transferase inhibitor, is a promising candidate to target HRAS-mutant tumours and should be explored in NSCLC patients.
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23
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Issahaku AR, Salifu EY, Soliman MES. Inside the cracked kernel: establishing the molecular basis of AMG510 and MRTX849 in destabilising KRASG12C mutant switch I and II in cancer treatment. J Biomol Struct Dyn 2022:1-13. [PMID: 35543250 DOI: 10.1080/07391102.2022.2074141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent targeting, the oncoprotein is being expunged from the 'undruggable' list of proteins. This feat has seen some covalent drugs at different stages of clinical trials. The advancement of AMG510 and MRTX849 as inhibitors of cysteine mutated KRAS (KRASG12C) to phase-III clinical trials informed the biased selection of AMG510 and MRTX849 for this study. Despite this advance, the molecular and atomistic modus operandi of these drugs is yet to come to light. In this study, we employed computational tools to unravel the atomistic interactions and subsequent conformational effects of AMG510 and MRTX849 on the mutant KRASG12C. It was revealed that AMG510 and MRTX849 complexes presented similar total free binding energies, (ΔGbind), of -88.15 ± 5.96 kcal/mol and -88.71 ± 7.70 kcal/mol, respectively. Gly10, Lys16, Thr58, Gly60, Glu62, Glu63, Arg68, Asp69, Met72, His95, Tyr96, Gln99, Arg102 and Val103 interacted prominently with AMG510 and MRTX849. These residues interacted with the pharmacophoric moieties of AMG510 and MRTX849 via hydrogen bonds with decreasing bond lengths at various stages of the simulation. These interactions together with pi-pi stacking, pi-sigma and pi-alkyl interactions induced unfolding of switch I whiles compacting switch II, which could interrupt the binding of effector proteins to these interfaces. These insights present useful atomistic perspectives into the success of AMG510 and MRTX849 which could guide the design of more selective and potent KRAS inhibitors.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Abdul Rashid Issahaku
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Elliasu Y Salifu
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Mahmoud E S Soliman
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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24
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Luo J, Ostrem J, Pellini B, Imbody D, Stern Y, Solanki HS, Haura EB, Villaruz LC. Overcoming KRAS-Mutant Lung Cancer. Am Soc Clin Oncol Educ Book 2022; 42:1-11. [PMID: 35412860 DOI: 10.1200/edbk_360354] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
More than 50 years after the discovery of RAS family proteins, which harbor the most common activating mutations in cancer, the U.S. Food and Drug Administration approved the first direct allele-specific inhibitor of mutant KRAS in lung cancer. We highlight the history of discovering RAS and decades of studies targeting KRAS-driven lung cancer. A landmark article by Shokat and colleagues in 2013 elucidated allosteric inhibition of this undruggable target and paved the way for the first-in-class direct KRASG12C inhibitor. Although these drugs have impressive 36%-45% objective response rates with a median duration of response of 10 months, many tumors do not respond, and diverse mechanisms of resistance have already been observed; this includes new KRAS alterations, activation of alternate RTK pathway proteins, bypass pathways, and transcriptional remodeling. These resistance mechanisms can be profiled using tissue-based and plasma-based testing and help to inform clinical trial options for patients. We conclude with a discussion of research informing ongoing clinical trials to rationally test promising treatments to thwart or overcome resistance to KRASG12C inhibitors and target other KRAS-altered lung cancers.
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Affiliation(s)
- Jia Luo
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Jonathan Ostrem
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Bruna Pellini
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Denis Imbody
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Yaakov Stern
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Hitendra S Solanki
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Eric B Haura
- Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL
| | - Liza C Villaruz
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA
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25
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Désage AL, Léonce C, Swalduz A, Ortiz-Cuaran S. Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies. Front Oncol 2022; 12:796832. [PMID: 35251972 PMCID: PMC8889932 DOI: 10.3389/fonc.2022.796832] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/07/2022] [Indexed: 12/17/2022] Open
Abstract
Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.
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Affiliation(s)
- Anne-Laure Désage
- Univ Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.,Department of Pulmonology and Thoracic Oncology, North Hospital, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Camille Léonce
- Univ Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France
| | - Aurélie Swalduz
- Univ Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.,Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Sandra Ortiz-Cuaran
- Univ Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France
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26
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Ferrara MG, Stefani A, Pilotto S, Carbone C, Vita E, Di Salvatore M, D'Argento E, Sparagna I, Monaca F, Valente G, Vitale A, Piro G, Belluomini L, Milella M, Tortora G, Bria E. The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures. Front Oncol 2022; 11:792385. [PMID: 35004317 PMCID: PMC8733471 DOI: 10.3389/fonc.2021.792385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) represents the perfect paradigm of ‘precision medicine’ due to its complex intratumoral heterogeneity. It is truly characterized by a range of molecular alterations that can deeply influence the natural history of this disease. Several molecular alterations have been found over time, paving the road to biomarker-driven therapy and radically changing the prognosis of ‘oncogene addicted’ NSCLC patients. Kirsten rat sarcoma (KRAS) mutations are present in up to 30% of NSCLC (especially in adenocarcinoma histotype) and have been identified decades ago. Since its discovery, its molecular characteristics and its marked affinity to a specific substrate have led to define KRAS as an undruggable alteration. Despite that, many attempts have been made to develop drugs capable of targeting KRAS signaling but, until a few years ago, these efforts have been unsuccessful. Comprehensive genomic profiling and wide-spectrum analysis of genetic alterations have only recently allowed to identify different types of KRAS mutations. This tricky step has finally opened new frontiers in the treatment approach of KRAS-mutant patients and might hopefully increase their prognosis and quality of life. In this review, we aim to highlight the most interesting aspects of (epi)genetic KRAS features, hoping to light the way to the state of art of targeting KRAS in NSCLC.
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Affiliation(s)
- Miriam Grazia Ferrara
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Alessio Stefani
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Sara Pilotto
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Carmine Carbone
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Emanuele Vita
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | | | - Ettore D'Argento
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Ileana Sparagna
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Federico Monaca
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Giustina Valente
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Antonio Vitale
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Geny Piro
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Lorenzo Belluomini
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Michele Milella
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
| | - Emilio Bria
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.,Section of Oncology, Department of Translational Medicine, Università Cattolica Del Sacro Cuore, Roma, Italy
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Rajpurohit T, Bhattacharya S. Moving Towards Dawn: KRas Signaling and Treatment in Pancreatic Ductal Adenocarcinoma. Curr Mol Pharmacol 2022; 15:904-928. [PMID: 35088684 DOI: 10.2174/1874467215666220128161647] [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: 07/26/2021] [Revised: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022]
Abstract
"Pancreatic ductal adenocarcinoma (PDAC)" is robust, nearly clueless, and all-around deadly among all tumors. Below 10 %, the general 5-year endurance period has remained adamantly unaltered in the last 30 years, regardless of enormous clinical and therapeutic endeavors. The yearly number of deaths is more than the number of recently analyzed cases. Not a classic one, but "Carbohydrate Antigen CA19- 9" remains the prevailing tool for diagnosis. MicroRNAs and non-invasive techniques are now incorporated for the effective prognosis of PDAC than just CA19-9. Mutated "Rat sarcoma virus Ras" conformation "V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog KRas" is 95 % accountable for PDAC, and its active (GTP-bound) formation activates signaling cascade comprising "Rapidly accelerated fibrosarcoma Raf"/"Mitogen-activated protein kinase MEK"/ "Extracellular signal-regulated kinase ERK" with "Phosphoinositide 3-kinase PI3K"/ "protein kinase B Akt"/ "mammalian target of rapamycin mTOR" pathways. KRas has acquired the label of 'undruggable' since the crosstalk in the nexus of pathways compensates for Raf and PI3K signaling cascade blocking. It is arduous to totally regulate KRascoordinated PDAC with traditional medicaments like "gemcitabine GEM" plus nabpaclitaxel/ FOLFIRINOX. For long-haul accomplishments aiming at KRas, future endeavors should be directed to combinatorial methodologies to adequately block KRas pathways at different standpoints. Currently they are contributing to healing PDAC. In this review article, we outline the function of KRas in carcinogenesis in PDAC, its signaling cascade, former techniques utilized in hindering Kras, current and future possibilities for targeting Kras.
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Affiliation(s)
- Tarun Rajpurohit
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
| | - Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
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Ritu K, Kumar P, Singh A, Nupur K, Spalgias S, Mrigpuri P, Rajkumar. Untangling the KRAS mutated lung cancer subsets and its therapeutic implications. MOLECULAR BIOMEDICINE 2021; 2:40. [PMID: 34918209 PMCID: PMC8677854 DOI: 10.1186/s43556-021-00061-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
The Kirsten rat sarcoma virus transforming protein (KRAS) mutations (predominate in codons 12, 13, and 61) and genomically drive nearly one-third of lung carcinomas. These mutations have complex functions in tumorigenesis, and influence the tumor response to chemotherapy and tyrosine kinase inhibitors resulting in a poorer patient prognosis. Recent attempts using targeted therapies against KRAS alone have met with little success. The existence of specific subsets of lung cancer based on KRAS mutations and coexisting mutations are suggested. Their interactions need further elaboration before newer promising targeted therapies for KRAS mutant lung cancers can be used as earlier lines of therapy. We summarize the existing knowledge of KRAS mutations and their coexisting mutations that is relevant to lung cancer treatment, in this review. We elaborate on the prognostic impact of clinical and pathologic characteristics of lung cancer patients associated with KRAS mutations. We briefly review the currently available techniques for KRAS mutation detection on biopsy and cytology samples. Finally, we discuss the new therapeutic strategies for targeting KRAS-mutant non-small cell lung cancer (NSCLC). These may herald a new era in the treatment of KRASG12Cmutated NSCLC as well as be helpful to develop demographic subsets to predict targeted therapies and prognosis of lung cancer patients.
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Jacobs F, Cani M, Malapelle U, Novello S, Napoli VM, Bironzo P. Targeting KRAS in NSCLC: Old Failures and New Options for "Non-G12c" Patients. Cancers (Basel) 2021; 13:6332. [PMID: 34944952 PMCID: PMC8699276 DOI: 10.3390/cancers13246332] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease.
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Affiliation(s)
- Francesca Jacobs
- Department of Oncology, University of Turin, AOU San Luigi Gonzaga, 10043 Turin, Italy; (F.J.); (M.C.); (S.N.); (V.M.N.)
| | - Massimiliano Cani
- Department of Oncology, University of Turin, AOU San Luigi Gonzaga, 10043 Turin, Italy; (F.J.); (M.C.); (S.N.); (V.M.N.)
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, 80138 Naples, Italy;
| | - Silvia Novello
- Department of Oncology, University of Turin, AOU San Luigi Gonzaga, 10043 Turin, Italy; (F.J.); (M.C.); (S.N.); (V.M.N.)
| | - Valerio Maria Napoli
- Department of Oncology, University of Turin, AOU San Luigi Gonzaga, 10043 Turin, Italy; (F.J.); (M.C.); (S.N.); (V.M.N.)
| | - Paolo Bironzo
- Department of Oncology, University of Turin, AOU San Luigi Gonzaga, 10043 Turin, Italy; (F.J.); (M.C.); (S.N.); (V.M.N.)
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Nagasaka M, Potugari B, Nguyen A, Sukari A, Azmi AS, Ou SHI. KRAS Inhibitors- yes but what next? Direct targeting of KRAS- vaccines, adoptive T cell therapy and beyond. Cancer Treat Rev 2021; 101:102309. [PMID: 34715449 DOI: 10.1016/j.ctrv.2021.102309] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 12/12/2022]
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.
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Affiliation(s)
- Misako Nagasaka
- University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA; Division of Neurology, Department of Internal Medicine, St. Marianna University, Kawasaki, Japan.
| | - Bindu Potugari
- Department of Hematology and Oncology, St. Joseph Mercy Health System, Ann Arbor, MI, USA
| | - Alexis Nguyen
- Wayne State University School of Medicine, Detroit, MI, USA
| | | | - Asfar S Azmi
- Wayne State University School of Medicine, Detroit, MI, USA; Karmanos Cancer Institute, Detroit, MI, USA
| | - Sai-Hong Ignatius Ou
- University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA
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Kessler L, Malik S, Leoni M, Burrows F. Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas. Cancers (Basel) 2021; 13:cancers13215310. [PMID: 34771475 PMCID: PMC8582567 DOI: 10.3390/cancers13215310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 11/16/2022] Open
Abstract
Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)-specifically, tumors that express a mutation in the HRAS protooncogene. More recently, bioinformatic analyses and results from patient-derived xenograft modeling indicate that HRAS pathway dependency may extend to a broader subpopulation of SCCs beyond HRAS mutants in the context of combination with agents such as cisplatin, cetuximab, or alpelisib. In addition, tipifarnib can also inactivate additional farnesylated proteins implicated in resistance to approved therapies, including immunotherapies, through a variety of distinct mechanisms, suggesting that tipifarnib could serve as an anchor for combination regimens in SCCs and other tumor types.
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32
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Rodak O, Peris-Díaz MD, Olbromski M, Podhorska-Okołów M, Dzięgiel P. Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy. Cancers (Basel) 2021; 13:4705. [PMID: 34572931 PMCID: PMC8470525 DOI: 10.3390/cancers13184705] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe region-dependent differences related to the education and the economic level of the patients. Due to an increasing understanding of NSCLC biology, new diagnostic and therapeutic strategies have been developed, such as the reorganization of histopathological classification or tumor genotyping. Precision medicine is focused on the recognition of a genetic mutation in lung cancer cells called "driver mutation" to provide a variety of specific inhibitors of improperly functioning proteins. A rapidly growing group of approved drugs for targeted therapy in NSCLC currently allows the following mutated proteins to be treated: EGFR family (ERBB-1, ERBB-2), ALK, ROS1, MET, RET, NTRK, and RAF. Nevertheless, one of the most frequent NSCLC molecular sub-types remains without successful treatment: the K-Ras protein. In this review, we discuss the current NSCLC landscape treatment focusing on targeted therapy and immunotherapy, including first- and second-line monotherapies, immune checkpoint inhibitors with chemotherapy treatment, and approved predictive biomarkers.
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Affiliation(s)
- Olga Rodak
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.O.); (P.D.)
| | - Manuel David Peris-Díaz
- Department of Chemical Biology, Faculty of Biotechnology, University of Wroclaw, F. Joliot-Curie 14a, 50-383 Wroclaw, Poland;
| | - Mateusz Olbromski
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.O.); (P.D.)
| | - Marzenna Podhorska-Okołów
- Department of Ultrastructural Research, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Piotr Dzięgiel
- Department of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland; (M.O.); (P.D.)
- Department of Physiotherapy, University School of Physical Education, 51-612 Wroclaw, Poland
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Lindsay CR, Garassino MC, Nadal E, Öhrling K, Scheffler M, Mazières J. On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma. Lung Cancer 2021; 160:152-165. [PMID: 34417059 DOI: 10.1016/j.lungcan.2021.07.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/07/2021] [Accepted: 07/10/2021] [Indexed: 12/25/2022]
Abstract
Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer death. Approximately one-third of patients with NSCLC have a KRAS mutation. KRASG12C, the most common mutation, is found in ~13% of patients. While KRAS was long considered 'undruggable', several novel direct KRASG12C inhibitors have shown encouraging signs of efficacy in phase I/II trials and one of these (sotorasib) has recently been approved by the US Food and Drug Administration. This review examines the role of KRAS mutations in NSCLC and the challenges in targeting KRAS. Based on specific KRAS biology, it reports exciting progress, exploring the use of novel direct KRAS inhibitors as monotherapy or in combination with other targeted therapies, chemotherapy, and immunotherapy.
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Affiliation(s)
- Colin R Lindsay
- Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK.
| | | | - Ernest Nadal
- Department of Medical Oncology, Catalan Institute of Oncology, Duran i Reynals Hospital, Barcelona, Spain
| | | | - Matthias Scheffler
- Department I of Internal Medicine, Center for Integrated Oncology, and Lung Cancer Group, University Hospital of Cologne, Cologne, Germany
| | - Julien Mazières
- Service de Pneumologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
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Abstract
KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRAS-related studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRAS-mutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.
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Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol 2021; 32:1101-1110. [PMID: 34089836 DOI: 10.1016/j.annonc.2021.06.001] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/18/2021] [Accepted: 06/01/2021] [Indexed: 02/07/2023] Open
Abstract
Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.
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Affiliation(s)
- M Reck
- Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany.
| | - D P Carbone
- James Thoracic Oncology Center, The Ohio State University, Columbus, USA
| | - M Garassino
- Department of Medicine, Section Hematology Oncology; The University of Chicago, Chicago, USA
| | - F Barlesi
- Aix Marseille University, Marseille, France; Gustave Roussy Cancer Campus, Villejuif, France
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36
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Malapelle U, Passiglia F, Cremolini C, Reale ML, Pepe F, Pisapia P, Avallone A, Cortinovis D, De Stefano A, Fassan M, Fontanini G, Galetta D, Lauricella C, Listì A, Loupakis F, Pagni F, Pietrantonio F, Pilotto S, Righi L, Bianchi AS, Parra HS, Tiseo M, Verzè M, Troncone G, Novello S. RAS as a positive predictive biomarker: focus on lung and colorectal cancer patients. Eur J Cancer 2021; 146:74-83. [PMID: 33588147 DOI: 10.1016/j.ejca.2021.01.015] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 12/27/2020] [Accepted: 01/07/2021] [Indexed: 02/07/2023]
Abstract
Rat sarcoma (RAS) oncogenes have intensively been investigated during the last decades. Taking into account all human tumours, Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene is the most frequently mutated (about 22%) among the three isoforms, followed by Neuroblastoma RAS Viral Oncogene Homolog (NRAS) (8%) and Harvey Rat Sarcoma Viral Oncogene Homolog (HRAS) (3%). In the last years, careful attention has been paid on KRAS and NRAS gene mutations in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients because of their prognostic and predictive roles. In particular, a large body of literature data has been generated investigating clinical outcomes of targeted treatments in NSCLC and CRC KRAS- and NRAS-mutated patients. The latest evidences are here reviewed, providing also an overview of the real-world RAS mutation testing practice across different Italian laboratories. On this basis, we propose a knowledge-based system, www.rasatlas.com, to support the healthcare personnel in the management of patients featuring RAS gene mutations in the landscape of precision oncology.
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Affiliation(s)
- Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Francesco Passiglia
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy; Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Maria Lucia Reale
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
| | - Francesco Pepe
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Pasquale Pisapia
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G.Pascale, Napoli, Italia
| | - Diego Cortinovis
- SC Oncologia Medica, SS Lung Unit Asst Ospedale San Gerardo, Monza, Italy
| | - Alfonso De Stefano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G.Pascale, Napoli, Italia
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Gabriella Fontanini
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
| | - Domenico Galetta
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy
| | - Calogero Lauricella
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Angela Listì
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
| | - Fotios Loupakis
- Unit of Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Fabio Pagni
- Department of Medicine and Surgery, Pathology, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Sara Pilotto
- U.O.C. of Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy
| | - Luisella Righi
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
| | - Andrea Sartore Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milano, Italy; Oncology and Hemato-oncology Department, University of Milan, Milan, Italy
| | - Hector Soto Parra
- Department of Oncology, Medical Oncology, University Hospital Policlinico-San Marco, Catania, Italy
| | - Marcello Tiseo
- Department of Medicine and Surgery, Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Michela Verzè
- Department of Medicine and Surgery, Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy.
| | - Silvia Novello
- Department of Oncology, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy
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Salgia R, Pharaon R, Mambetsariev I, Nam A, Sattler M. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Rep Med 2021; 2:100186. [PMID: 33521700 PMCID: PMC7817862 DOI: 10.1016/j.xcrm.2020.100186] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
KRAS is a frequent oncogenic driver in solid tumors, including non-small cell lung cancer (NSCLC). It was previously thought to be an "undruggable" target due to the lack of deep binding pockets for specific small-molecule inhibitors. A better understanding of the mechanisms that drive KRAS transformation, improved KRAS-targeted drugs, and immunological approaches that aim at yielding immune responses against KRAS neoantigens have sparked a race for approved therapies. Few treatments are available for KRAS mutant NSCLC patients, and several approaches are being tested in clinicals trials to fill this void. Here, we review promising therapeutics tested for KRAS mutant NSCLC.
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Affiliation(s)
- Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Rebecca Pharaon
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Arin Nam
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Martin Sattler
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Surgery, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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38
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Dunnett-Kane V, Nicola P, Blackhall F, Lindsay C. Mechanisms of Resistance to KRAS G12C Inhibitors. Cancers (Basel) 2021; 13:E151. [PMID: 33466360 PMCID: PMC7795113 DOI: 10.3390/cancers13010151] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022] Open
Abstract
KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.
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Affiliation(s)
- Victoria Dunnett-Kane
- Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK;
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK; (P.N.); (F.B.)
| | - Pantelis Nicola
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK; (P.N.); (F.B.)
- Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
| | - Fiona Blackhall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK; (P.N.); (F.B.)
- Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester M20 4BX, UK
| | - Colin Lindsay
- Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK; (P.N.); (F.B.)
- Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
- Cancer Research UK Lung Cancer Centre of Excellence, Manchester M20 4BX, UK
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Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives. Biomolecules 2020; 10:biom10111535. [PMID: 33182807 PMCID: PMC7698260 DOI: 10.3390/biom10111535] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/03/2020] [Accepted: 11/08/2020] [Indexed: 02/07/2023] Open
Abstract
RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources.
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Uprety D, Adjei AA. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev 2020; 89:102070. [DOI: 10.1016/j.ctrv.2020.102070] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/04/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
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Passiglia F, Malapelle U, Del Re M, Righi L, Pagni F, Furlan D, Danesi R, Troncone G, Novello S. KRAS inhibition in non-small cell lung cancer: Past failures, new findings and upcoming challenges. Eur J Cancer 2020; 137:57-68. [PMID: 32745965 DOI: 10.1016/j.ejca.2020.06.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 06/08/2020] [Accepted: 06/18/2020] [Indexed: 02/07/2023]
Abstract
Despite the high prevalence of Kirsten rat sarcoma (KRAS) mutations in non-small cell lung cancer (NSCLC), for a long time it has been defined as an 'undruggable target', with precision medicine not considered as an adequate approach to treat this subgroup of patients. After several years of efforts, preliminary data from early clinical trials have recently demonstrated that direct pharmacological inhibition of KRAS p.G12C mutation is possible, emerging as an effective targeted treatment for about 10-12% of patients with advanced NSCLC, with potential relevant impact on their long-term survival and quality of life. This review reports the current status of KRAS mutations detection in the Italian real-word scenario, summarises the biological basis of KRAS inhibition in NSCLC and provides an updated overview of therapeutic strategies, discussing the potential reasons for past failures and analysing the upcoming challenges related to the advent of new targeted agents in clinical practice.
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Affiliation(s)
- Francesco Passiglia
- Department of Oncology, University of Turin, S. Luigi Gonzaga Hospital, Orbassano (TO), Italy.
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy.
| | - Marzia Del Re
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Italy.
| | - Luisella Righi
- Department of Oncology, University of Turin, S. Luigi Gonzaga Hospital, Orbassano (TO), Italy.
| | - Fabio Pagni
- Department of Medicine and Surgery, Pathology, San Gerardo Hospital, University of Milano- Bicocca, 20900 Monza, Italy.
| | - Daniela Furlan
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, 21100, Varese, Italy.
| | - Romano Danesi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Italy.
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy.
| | - Silvia Novello
- Department of Oncology, University of Turin, S. Luigi Gonzaga Hospital, Orbassano (TO), Italy.
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Abstract
RAS was identified as a human oncogene in the early 1980s and subsequently found to be mutated in nearly 30% of all human cancers. More importantly, RAS plays a central role in driving tumor development and maintenance. Despite decades of effort, there remain no FDA approved drugs that directly inhibit RAS. The prevalence of RAS mutations in cancer and the lack of effective anti-RAS therapies stem from RAS' core role in growth factor signaling, unique structural features, and biochemistry. However, recent advances have brought promising new drugs to clinical trials and shone a ray of hope in the field. Here, we will exposit the details of RAS biology that illustrate its key role in cell signaling and shed light on the difficulties in therapeutically targeting RAS. Furthermore, past and current efforts to develop RAS inhibitors will be discussed in depth.
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Affiliation(s)
- J Matthew Rhett
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson VA Medical Center, Charleston, SC, United States
| | - Imran Khan
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson VA Medical Center, Charleston, SC, United States
| | - John P O'Bryan
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson VA Medical Center, Charleston, SC, United States.
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Uras IZ, Moll HP, Casanova E. Targeting KRAS Mutant Non-Small-Cell Lung Cancer: Past, Present and Future. Int J Mol Sci 2020; 21:E4325. [PMID: 32560574 PMCID: PMC7352653 DOI: 10.3390/ijms21124325] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Lung cancer is the most frequent cancer with an aggressive clinical course and high mortality rates. Most cases are diagnosed at advanced stages when treatment options are limited and the efficacy of chemotherapy is poor. The disease has a complex and heterogeneous background with non-small-cell lung cancer (NSCLC) accounting for 85% of patients and lung adenocarcinoma being the most common histological subtype. Almost 30% of adenocarcinomas of the lung are driven by an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. The ability to inhibit the oncogenic KRAS has been the holy grail of cancer research and the search for inhibitors is immensely ongoing as KRAS-mutated tumors are among the most aggressive and refractory to treatment. Therapeutic strategies tailored for KRAS+ NSCLC rely on the blockage of KRAS functional output, cellular dependencies, metabolic features, KRAS membrane associations, direct targeting of KRAS and immunotherapy. In this review, we provide an update on the most recent advances in anti-KRAS therapy for lung tumors with mechanistic insights into biological diversity and potential clinical implications.
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Affiliation(s)
- Iris Z. Uras
- Department of Pharmacology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090 Vienna, Austria
| | - Herwig P. Moll
- Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090 Vienna, Austria; (H.P.M.); (E.C.)
| | - Emilio Casanova
- Department of Physiology, Center of Physiology and Pharmacology & Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090 Vienna, Austria; (H.P.M.); (E.C.)
- Ludwig Boltzmann Institute for Cancer Research (LBI-CR), 1090 Vienna, Austria
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Salgia R, Mambetsariev I, Tan T, Schwer A, Pearlstein DP, Chehabi H, Baroz A, Fricke J, Pharaon R, Romo H, Waddington T, Babikian R, Buck L, Kulkarni P, Cianfrocca M, Djulbegovic B, Pal SK. Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting-Role of Academic and Hybrid Modeling. J Clin Med 2020; 9:E1884. [PMID: 32560187 PMCID: PMC7356888 DOI: 10.3390/jcm9061884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/24/2022] Open
Abstract
Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy.
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Affiliation(s)
- Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Tingting Tan
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Amanda Schwer
- Newport Diagnostic Center, Newport Beach, CA 92660, USA; (A.S.); (H.C.)
| | | | - Hazem Chehabi
- Newport Diagnostic Center, Newport Beach, CA 92660, USA; (A.S.); (H.C.)
| | - Angel Baroz
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Jeremy Fricke
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Rebecca Pharaon
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Hannah Romo
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Thomas Waddington
- Department of Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Razmig Babikian
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Linda Buck
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Prakash Kulkarni
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Mary Cianfrocca
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Benjamin Djulbegovic
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Sumanta K. Pal
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
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45
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Adderley H, Blackhall FH, Lindsay CR. KRAS-mutant non-small cell lung cancer: Converging small molecules and immune checkpoint inhibition. EBioMedicine 2019; 41:711-716. [PMID: 30852159 PMCID: PMC6444074 DOI: 10.1016/j.ebiom.2019.02.049] [Citation(s) in RCA: 135] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 02/19/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023] Open
Abstract
KRAS is the most frequent oncogene in non-small cell lung cancer (NSCLC), a molecular subset characterized by historical disappointments in targeted treatment approaches such as farnesyl transferase inhibition, downstream MEK inhibition, and synthetic lethality screens. Unlike other important mutational subtypes of NSCLC, preclinical work supports the hypothesis that KRAS mutations may be vulnerable to immunotherapy approaches, an efficacy associated in particular with TP53 co-mutation. In this review we detail reasons for previous failures in KRAS-mutant NSCLC, evidence to suggest that KRAS mutation is a genetic marker of benefit from immune checkpoint inhibition, and emerging direct inhibitors of K-Ras which will soon be combined with immunotherapy during clinical development. With signs of real progress in this subgroup of unmet need, we anticipate that KRAS mutant NSCLC will be the most important molecular subset of cancer to evaluate the combination of small molecules and immune checkpoint inhibitors (CPI).
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Jazieh K, Molina J, Allred J, Yin J, Reid J, Goetz M, Lim VS, Kaufmann SH, Adjei A. A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors. Invest New Drugs 2018; 37:307-314. [DOI: 10.1007/s10637-018-0662-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 08/22/2018] [Indexed: 10/28/2022]
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Lindsay CR, Jamal-Hanjani M, Forster M, Blackhall F. KRAS: Reasons for optimism in lung cancer. Eur J Cancer 2018; 99:20-27. [PMID: 29894909 DOI: 10.1016/j.ejca.2018.05.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 03/21/2018] [Accepted: 05/13/2018] [Indexed: 01/07/2023]
Abstract
Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon. It now seems clear that mutational subtype (most commonly G12C) of individual mutations is of greater relevance than the categorical evaluation of KRAS mutation presence or otherwise. A number of direct small molecules targeted to these subtypes are in development and have shown promising biological activity, with some in the late stages of preclinical validation.
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Affiliation(s)
- C R Lindsay
- Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, UK.
| | - M Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, UK; Department of Oncology, University College of London Hospital and UCL Cancer Institute, London, UK
| | - M Forster
- Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, UK; Department of Oncology, University College of London Hospital and UCL Cancer Institute, London, UK
| | - F Blackhall
- Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, London and Manchester, UK
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KRAS-Mutant non-small cell lung cancer: From biology to therapy. Lung Cancer 2018; 124:53-64. [PMID: 30268480 DOI: 10.1016/j.lungcan.2018.07.013] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 07/09/2018] [Accepted: 07/11/2018] [Indexed: 12/30/2022]
Abstract
In patients with non-small cell lung cancer (NSCLC), the most frequent oncogene driver mutation in Western countries is Kirsten rat sarcoma viral oncogene homolog (KRAS), and KRAS-mutant NSCLC is associated with smoking. There are various sources of biological heterogeneity of KRAS-mutant NSCLC, including different genotypes that may be associated with specific clinical outcomes, the presence of other co-mutations that exhibit different biological features and drug sensitivity patterns, and mutant allelic content. The efficacy of chemotherapy in patients with KRAS-mutant NSCLC is generally poor and numerous novel therapeutic strategies have been developed. These approaches include targeting KRAS membrane associations, targeting downstream signalling pathways, the use of KRAS synthetic lethality, direct targeting of KRAS, and immunotherapy. Of these, immunotherapy may be one of the most promising treatment approaches for patients with KRAS-mutant NSCLC. Recent data also suggest the potential for distinct efficacy of immunotherapy according to the presence of other co-mutations. In view of the biological heterogeneity of KRAS-mutant NSCLC, treatment will likely need to be individualised and, in future, may require the use of rational combinations of treatment, many of which are currently under investigation.
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Aredo JV, Padda SK. Management of KRAS-Mutant Non-Small Cell Lung Cancer in the Era of Precision Medicine. Curr Treat Options Oncol 2018; 19:43. [PMID: 29951788 DOI: 10.1007/s11864-018-0557-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OPINION STATEMENT The discovery of genomic alterations that drive the development and progression of non-small cell lung cancer (NSCLC) has transformed how we treat metastatic disease. However, the promise of precision medicine remains elusive for the most commonly mutated oncogene in NSCLC, KRAS. This is perhaps due to the substantial heterogeneity within the broader genomic context of KRAS-mutant NSCLC. At this time, approaches for treating metastatic KRAS-mutant NSCLC mirror those for treating NSCLC that lacks a known driver mutation, including standard chemotherapeutic and immunotherapeutic approaches. Ongoing research aims to define further subgroups of KRAS-mutant NSCLC based on mutation subtype and co-occurring mutations. These efforts offer the potential to optimize standard-of-care regimens within these emerging subgroups and harness innovative strategies to realize precision medicine in this setting.
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Affiliation(s)
- Jacqueline V Aredo
- Department of Medicine, Division of Oncology, Stanford Cancer Institute/Stanford University School of Medicine, 875 Blake Wilbur Drive, Stanford, CA, 94305, USA
| | - Sukhmani K Padda
- Department of Medicine, Division of Oncology, Stanford Cancer Institute/Stanford University School of Medicine, 875 Blake Wilbur Drive, Stanford, CA, 94305, USA.
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50
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Montor WR, Salas AROSE, Melo FHMD. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol Cancer 2018; 17:55. [PMID: 29455659 PMCID: PMC5817866 DOI: 10.1186/s12943-018-0792-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 02/01/2018] [Indexed: 12/23/2022] Open
Abstract
Searching for targets that allow pharmacological inhibition of cell proliferation in over-proliferative states, such as cancer, leads us to finely understand the complex mechanisms orchestrating the perfect control of mitosis number, frequency and pace as well as the molecular arrangements that induce cells to enter functional quiescence and brings them back to cycling in specific conditions. Although the mechanisms regulating cell proliferation have been described several years ago, never before has so much light been shed over this machinery as during the last decade when therapy targets have been explored and molecules, either synthetic or in the form of antibodies with the potential of becoming cancer drugs were produced and adjusted for specific binding and function. Proteins containing tyrosine kinase domains, either membrane receptors or cytoplasmic molecules, plus the ones activated by those in downstream pathways, having tyrosine kinase domains or not, such as RAS which is a GTPase and serine/threonine kinases such as RAF, play crucial role in conducting proliferation information from cell surroundings to the nucleus where gene expression takes place. Tyrosine kinases phosphorylate tyrosine residues in an activating mode and are found in important growth factor receptors, such as for ligands from families collectively known as VEGF, PDGF and EGF, to name a few and in intracellular downstream molecules. They all play important roles in normal physiology and are commonly found mutated or overexpressed in neoplastic states. Our objective here is to present such kinases as druggable targets for cancer therapy, highlighting the ones for which the pharmacological arsenal is available, discussing specificity, resistance mechanisms and treatment alternatives in cases of resistance, plus listing potential targets that have not been successfully worked yet.
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Affiliation(s)
- Wagner Ricardo Montor
- Departamento de Ciências Fisiológicas, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, Brazil
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