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1
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Mo C, Sterpi M, Jeon H, Bteich F. Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies. Cancers (Basel) 2024; 16:2854. [PMID: 39199625 PMCID: PMC11352490 DOI: 10.3390/cancers16162854] [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: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.
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Affiliation(s)
- Christiana Mo
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Michelle Sterpi
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Hyein Jeon
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
| | - Fernand Bteich
- Department of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; (C.M.); (M.S.); (H.J.)
- Department of Medical Oncology, Montefiore Medical Center, Bronx, NY 10467, USA
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2
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Scheck MK, Hofheinz RD, Lorenzen S. HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments. Cancers (Basel) 2024; 16:1336. [PMID: 38611014 PMCID: PMC11010911 DOI: 10.3390/cancers16071336] [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: 02/07/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.
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Affiliation(s)
- Magdalena K. Scheck
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
| | - Ralf D. Hofheinz
- Mannheim Cancer Center, Universitätsklinikum Mannheim, 68167 Mannheim, Germany;
| | - Sylvie Lorenzen
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
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3
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Shaban N, Kamashev D, Emelianova A, Buzdin A. Targeted Inhibitors of EGFR: Structure, Biology, Biomarkers, and Clinical Applications. Cells 2023; 13:47. [PMID: 38201251 PMCID: PMC10778338 DOI: 10.3390/cells13010047] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Members of the EGFR family of tyrosine kinase receptors are major regulators of cellular proliferation, differentiation, and survival. In humans, abnormal activation of EGFR is associated with the development and progression of many cancer types, which makes it an attractive target for molecular-guided therapy. Two classes of EGFR-targeted cancer therapeutics include monoclonal antibodies (mAbs), which bind to the extracellular domain of EGFR, and tyrosine kinase inhibitors (TKIs), which mostly target the intracellular part of EGFR and inhibit its activity in molecular signaling. While EGFR-specific mAbs and three generations of TKIs have demonstrated clinical efficacy in various settings, molecular evolution of tumors leads to apparent and sometimes inevitable resistance to current therapeutics, which highlights the need for deeper research in this field. Here, we tried to provide a comprehensive and systematic overview of the rationale, molecular mechanisms, and clinical significance of the current EGFR-targeting drugs, highlighting potential candidate molecules in development. We summarized the underlying mechanisms of resistance and available personalized predictive approaches that may lead to improved efficacy of EGFR-targeted therapies. We also discuss recent developments and the use of specific therapeutic strategies, such as multi-targeting agents and combination therapies, for overcoming cancer resistance to EGFR-specific drugs.
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Affiliation(s)
- Nina Shaban
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (D.K.); (A.B.)
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
| | - Dmitri Kamashev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (D.K.); (A.B.)
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
| | - Aleksandra Emelianova
- World-Class Research Center “Digital Biodesign and Personalized Healthcare”, Sechenov First Moscow State Medical University, Moscow 119991, Russia;
| | - Anton Buzdin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia; (D.K.); (A.B.)
- Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia
- Institute of Personalized Oncology, I.M. Sechenov First Moscow State Medical University, Moscow 119991, Russia
- PathoBiology Group, European Organization for Research and Treatment of Cancer (EORTC), 1200 Brussels, Belgium
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4
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Mu Y, Meng Y, Du Y, Liu X, Zhang J. Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer. Thorac Cancer 2023; 14:3381-3388. [PMID: 37863840 PMCID: PMC10693943 DOI: 10.1111/1759-7714.15130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 09/25/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND The clinical characteristics and efficacy of human epidermal growth factor receptor-2 (HER-2)-directed agents against HER2 mutations and HER2 fusions in breast cancer are obscure due to their low frequency. METHODS We conducted a retrospective study in patients with advanced breast cancer harboring HER2 mutations and/or HER2 fusions between January 1, 2017 and January 1, 2021. RESULTS Among a total of 22 patients, 17 HER2 mutations were detected, including L755S, S310F, R100=, V777L, R897W, T862A, 440-17C > G, H878Y, V842I, 73 + 9G > C, T278fs, E1069K, L755P, 226-11C > T, 574 + 12C>T, L114V and P128L. The majority of patients had ductal carcinoma, which mostly coexisted with HER2 amplification/overexpression. The median progression-free survival (PFS) of the 22 patients was 6.9 months (95% CI: 4.7, 9.1) in the first-line setting. The median PFS of patients who received first-line trastuzumab-based regimens was significantly longer than that of patients who received a first-line tyrosine kinase inhibitor (TKI) (10.8 months [95% CI: 2.9, 18.7] vs. 1.9 months [95% CI: 0.8, 3.0], p < 0.005). A total of 14 patients were treated with anti-HER2 antibody-drug conjugate (ADC), among whom the median treatment line of first-time of administration of anti-HER2 ADC was 4.5 (range, 1-10). Anti-HER2 ADC reached an objective response rate (ORR) of 42.9%, a disease control rate (DCR) of 85.7% and a median PFS of 7.3 months (95% CI: 4.4-10.1) from the first-time of administration. CONCLUSION Our data demonstrated the clinical benefit of anti-HER2 treatment in Chinese breast cancer patients harboring HER2 mutation and/or HER2 fusion. The value of immunotherapy and treatment selection among individual HER2 variants needs further study.
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Affiliation(s)
- Yuxin Mu
- Phase I Clinical Trial CenterFudan University Shanghai Cancer CenterShanghaiChina
| | - Yanchun Meng
- Phase I Clinical Trial CenterFudan University Shanghai Cancer CenterShanghaiChina
| | - Yiqun Du
- Phase I Clinical Trial CenterFudan University Shanghai Cancer CenterShanghaiChina
| | - Xiaojun Liu
- Phase I Clinical Trial CenterFudan University Shanghai Cancer CenterShanghaiChina
| | - Jian Zhang
- Phase I Clinical Trial CenterFudan University Shanghai Cancer CenterShanghaiChina
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Majumder A. HER3: Toward the Prognostic Significance, Therapeutic Potential, Current Challenges, and Future Therapeutics in Different Types of Cancer. Cells 2023; 12:2517. [PMID: 37947595 PMCID: PMC10648638 DOI: 10.3390/cells12212517] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/14/2023] [Accepted: 10/20/2023] [Indexed: 11/12/2023] Open
Abstract
Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 is activated in a ligand-dependent (NRG1/HRG) or independent manner, it can bind to other receptors (the most potent binding partner is HER2) to regulate many biological functions (growth, survival, nutrient sensing, metabolic regulation, etc.) through the PI3K-AKT-mTOR pathway. HER3 has been found to promote tumorigenesis, tumor growth, and drug resistance in different cancer types, especially breast and non-small cell lung cancer. Given its ubiquitous expression across different solid tumors and role in oncogenesis and drug resistance, there has been a long effort to target HER3. As HER3 cannot be targeted through its KD with small-molecule kinase inhibitors via the conventional method, pharmaceutical companies have used various other approaches, including blocking either the ligand-binding domain or extracellular domain for dimerization with other receptors. The development of treatment options with anti-HER3 monoclonal antibodies, bispecific antibodies, and different combination therapies showed limited clinical efficiency for various reasons. Recent reports showed that the extracellular domain of HER3 is not required for its binding with other receptors, which raises doubt about the efforts and applicability of the development of the HER3-antibodies for treatment. Whereas HER3-directed antibody-drug conjugates showed potentiality for treatment, these drugs are still under clinical trial. The currently understood model for dimerization-induced signaling remains incomplete due to the absence of the crystal structure of HER3 signaling complexes, and many lines of evidence suggest that HER family signaling involves more than the interaction of two members. This review article will significantly expand our knowledge of HER3 signaling and shed light on developing a new generation of drugs that have fewer side effects than the current treatment regimen for these patients.
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Affiliation(s)
- Avisek Majumder
- Department of Medicine, University of California, San Francisco, CA 94158, USA
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6
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Moasser MM. Inactivating amplified HER2: challenges, dilemmas, and future directions. Cancer Res 2022; 82:2811-2820. [PMID: 35731927 DOI: 10.1158/0008-5472.can-22-1121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/10/2022] [Accepted: 06/15/2022] [Indexed: 11/16/2022]
Abstract
The pharmaceutical inactivation of driver oncogenes has revolutionized the treatment of cancer replacing cytotoxic chemotherapeutic approaches with kinase inhibitor therapies for many types of cancers. This approach has not yet been realized for the treatment of HER2-amplified cancers. The monotherapy activities associated with HER2-targeting antibodies and kinase inhibitors are modest, and their clinical use has been in combination with, and not in replacement of cytotoxic chemotherapies. This stands in sharp contrast to achievements in the treatment of many other oncogene-driven cancers. The mechanism-based treatment hypothesis regarding the inactivation of HER2 justifies expectations far beyond what is currently realized. Overcoming this barrier requires mechanistic insights that can fuel new directions for pursuit, but scientific investigation of this treatment hypothesis, particularly with regards to trastuzumab, has been complicated by conflicting and confusing data sets, ironclad dogma, and mechanistic conclusions that have repeatedly failed to translate clinically. We are now approaching a point of convergence regarding the challenges and resiliency in this tumor driver, and I will provide here a review and opinion to inform where we currently stand with this treatment hypothesis and where the future potential lies.
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Affiliation(s)
- Mark M Moasser
- University of California, San Francisco, San Francisco, CA, United States
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7
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Blangé D, Stroes CI, Derks S, Bijlsma MF, van Laarhoven HW. Resistance Mechanisms to HER2-Targeted Therapy in Gastroesophageal Adenocarcinoma: A Systematic Review. Cancer Treat Rev 2022; 108:102418. [DOI: 10.1016/j.ctrv.2022.102418] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/20/2022] [Accepted: 05/22/2022] [Indexed: 12/16/2022]
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8
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Campbell MR, Ruiz-Saenz A, Zhang Y, Peterson E, Steri V, Oeffinger J, Sampang M, Jura N, Moasser MM. Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling. Cell Rep 2022; 38:110285. [PMID: 35108526 PMCID: PMC8865943 DOI: 10.1016/j.celrep.2021.110285] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 08/30/2021] [Accepted: 12/28/2021] [Indexed: 12/13/2022] Open
Abstract
Surface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints.
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Affiliation(s)
- Marcia R Campbell
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ana Ruiz-Saenz
- Departments of Cell Biology & Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Yuntian Zhang
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Elliott Peterson
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Veronica Steri
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Julie Oeffinger
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Maryjo Sampang
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Natalia Jura
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Mark M Moasser
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
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9
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Tobias J, Garner-Spitzer E, Drinić M, Wiedermann U. Vaccination against Her-2/neu, with focus on peptide-based vaccines. ESMO Open 2022; 7:100361. [PMID: 35026721 PMCID: PMC8760406 DOI: 10.1016/j.esmoop.2021.100361] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/29/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022] Open
Abstract
Immunotherapy has been a milestone in combatting cancer, by complementing or even replacing classic treatments like surgery, chemotherapy, radiation, and anti-hormonal therapy. In 15%-30% of breast cancers, overexpression of the human epidermal growth factor receptor 2 (Her-2/neu) is associated with more aggressive tumor development. Passive immunization/immunotherapy with the recombinantly produced Her-2/neu-targeting monoclonal antibodies (mAbs) pertuzumab and trastuzumab has been shown to effectively treat breast cancer and lead to a significantly better prognosis. However, allergic and hypersensitivity reactions, cardiotoxicity, development of resistance, lack of immunological memory which results in continuous application over a long period, and cost-intensiveness are among the drawbacks associated with this treatment. Furthermore, intrinsic or acquired resistance is associated with the application of therapeutic mAbs, leading to the disease recurrence. Conversely, these drawbacks could be potentially overcome by vaccination, i.e. an active immunization/immunotherapy approach by activating the patient’s own immune system to target cancer, along with inducing immunological memory. This review aims to summarize the main approaches investigated and undertaken for the production of Her-2/neu vaccine candidates, with the main focus on peptide-based vaccines and their evaluation in clinical settings.
Her-2/neu is overexpressed in 10%-30% of breast and gastric cancer patients and this correlates with poor clinical outcomes. Passive application of trastuzumab and pertuzumab has outstandingly improved the Her-2/neu-related clinical outcomes. Treatment with mAbs is associated with frequent administration, cost-intensiveness, and resistance. Vaccination against Her-2/neu with e.g. mimotope- or peptide-based vaccines can alternatively overcome the mAbs’ drawbacks. Such alternatives may pave the way to therapeutics which could be used as monotherapy or in combination therapies with mAbs.
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Affiliation(s)
- J Tobias
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
| | - E Garner-Spitzer
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - M Drinić
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - U Wiedermann
- Institute of Specific Prophylaxis and Tropical Medicine, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
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10
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Lucas LM, Dwivedi V, Senfeld JI, Cullum RL, Mill CP, Piazza JT, Bryant IN, Cook LJ, Miller ST, Lott JH, Kelley CM, Knerr EL, Markham JA, Kaufmann DP, Jacobi MA, Shen J, Riese DJ. The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein. Pharmacol Rev 2022; 74:18-47. [PMID: 34987087 PMCID: PMC11060329 DOI: 10.1124/pharmrev.121.000381] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/15/2021] [Indexed: 12/11/2022] Open
Abstract
ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. SIGNIFICANCE STATEMENT: This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and ERBB4 mutants in staging and treating human tumors.
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Affiliation(s)
- Lauren M Lucas
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Vipasha Dwivedi
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jared I Senfeld
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Richard L Cullum
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Christopher P Mill
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - J Tyler Piazza
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Ianthe N Bryant
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Laura J Cook
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - S Tyler Miller
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - James H Lott
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Connor M Kelley
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Elizabeth L Knerr
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jessica A Markham
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - David P Kaufmann
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Megan A Jacobi
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jianzhong Shen
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - David J Riese
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
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11
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Wang BW, Huang CH, Liu LC, Cheng FJ, Wei YL, Lin YM, Wang YF, Wei CT, Chen Y, Chen YJ, Huang WC. Pim1 Kinase Inhibitors Exert Anti-Cancer Activity Against HER2-Positive Breast Cancer Cells Through Downregulation of HER2. Front Pharmacol 2021; 12:614673. [PMID: 34267653 PMCID: PMC8276059 DOI: 10.3389/fphar.2021.614673] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 06/17/2021] [Indexed: 11/25/2022] Open
Abstract
The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.
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Affiliation(s)
- Bo-Wei Wang
- Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Chih-Hao Huang
- Division of Breast Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Liang-Chih Liu
- Division of Breast Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Fang-Ju Cheng
- Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ya-Ling Wei
- Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Yueh-Ming Lin
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yu-Fei Wang
- Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ching-Ting Wei
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan
| | - Yeh Chen
- Institute of New Drug Development, China Medical University, Taichung, Taiwan
| | - Yun-Ju Chen
- School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan.,Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan
| | - Wei-Chien Huang
- Graduate Institute of Biomedical Sciences, Center for Molecular Medicine and Research Center for Cancer Biology, China Medical University, Taichung, Taiwan.,Drug Development Center, China Medical University, Taichung, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.,The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan
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12
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Abstract
Neuregulins, members of the largest subclass of growth factors of the epidermal growth factor family, mediate a myriad of cellular functions including survival, proliferation, and differentiation in normal tissues through binding to receptor tyrosine kinases of the ErbB family. However, aberrant neuregulin signaling in the tumor microenvironment is increasingly recognized as a key player in initiation and malignant progression of human cancers. In this chapter, we focus on the role of neuregulin signaling in the hallmarks of cancer, including cancer initiation and development, metastasis, as well as therapeutic resistance. Moreover, role of neuregulin signaling in the regulation of tumor microenvironment and targeting of neuregulin signaling in cancer from the therapeutic perspective are also briefly discussed.
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13
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Ou GY, Lin WW, Zhao WJ. Neuregulins in Neurodegenerative Diseases. Front Aging Neurosci 2021; 13:662474. [PMID: 33897409 PMCID: PMC8064692 DOI: 10.3389/fnagi.2021.662474] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/16/2021] [Indexed: 02/05/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are typically characterized by progressive neuronal loss and neurological dysfunctions in the nervous system, affecting both memory and motor functions. Neuregulins (NRGs) belong to the epidermal growth factor (EGF)-like family of extracellular ligands and they play an important role in the development, maintenance, and repair of both the central nervous system (CNS) and peripheral nervous system (PNS) through the ErbB signaling pathway. They also regulate multiple intercellular signal transduction and participate in a wide range of biological processes, such as differentiation, migration, and myelination. In this review article, we summarized research on the changes and roles of NRGs in neurodegenerative diseases, especially in AD. We elaborated on the structural features of each NRG subtype and roles of NRG/ErbB signaling networks in neurodegenerative diseases. We also discussed the therapeutic potential of NRGs in the symptom remission of neurodegenerative diseases, which may offer hope for advancing related treatment.
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Affiliation(s)
- Guan-yong Ou
- Center for Neuroscience, Shantou University Medical College, Shantou, China
| | - Wen-wen Lin
- Center for Neuroscience, Shantou University Medical College, Shantou, China
| | - Wei-jiang Zhao
- Center for Neuroscience, Shantou University Medical College, Shantou, China
- Cell Biology Department, Wuxi School of Medicine, Jiangnan University, Wuxi, China
- *Correspondence: Wei-jiang Zhao
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14
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Hart V, Gautrey H, Kirby J, Tyson-Capper A. HER2 splice variants in breast cancer: investigating their impact on diagnosis and treatment outcomes. Oncotarget 2020; 11:4338-4357. [PMID: 33245725 PMCID: PMC7679030 DOI: 10.18632/oncotarget.27789] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/10/2020] [Indexed: 02/07/2023] Open
Abstract
Overexpression of the HER2 receptor occurs in approximately 20% of breast cancer patients. HER2 positivity is associated with poor prognosis and aggressive tumour phenotypes, which led to rapid progress in HER2 targeted therapeutics and diagnostic testing. Whilst these advances have greatly increased patients' chances of survival, resistance to HER2 targeted therapies, be that intrinsic or acquired, remains a problem. Different forms of the HER2 protein exist within tumours in tandem and can display altered biological activities. Interest in HER2 variants in breast cancer increased when links between resistance to anti-HER2 therapies and a particular variant, Δ16-HER2, were identified. Moreover, the P100 variant potentially reduces the efficacy of the anti-HER2 therapy trastuzumab. Another variant, Herstatin, exhibits 'auto-inhibitory' behaviour. More recently, new HER2 variants have been identified and are currently being assessed for their pro- and anti-cancer properties. It is important when directing the care of patients to consider HER2 variants collectively. This review considers HER2 variants in the context of the tumour environment where multiple variants are co-expressed at altered ratios. This study also provides an up to date account of the landscape of HER2 variants and links this to patterns of resistance against HER2 therapies and treatment plans.
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Affiliation(s)
- Vic Hart
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Hannah Gautrey
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - John Kirby
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Alison Tyson-Capper
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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15
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Segers VFM, Dugaucquier L, Feyen E, Shakeri H, De Keulenaer GW. The role of ErbB4 in cancer. Cell Oncol (Dordr) 2020; 43:335-352. [PMID: 32219702 DOI: 10.1007/s13402-020-00499-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The epidermal growth factor receptor family consists of four members, ErbB1 (epidermal growth factor receptor-1), ErbB2, ErbB3, and ErbB4, which all have been found to play important roles in tumor development. ErbB4 appears to be unique among these receptors, because it is the only member with growth inhibiting properties. ErbB4 plays well-defined roles in normal tissue development, in particular the heart, the nervous system, and the mammary gland system. In recent years, information on the role of ErbB4 in a number of tumors has emerged and its general direction points towards a tumor suppressor role for ErbB4. However, there are some controversies and conflicting data, warranting a review on this topic. CONCLUSIONS Here, we discuss the role of ErbB4 in normal physiology and in breast, lung, colorectal, gastric, pancreatic, prostate, bladder, and brain cancers, as well as in hepatocellular carcinoma, cholangiocarcinoma, and melanoma. Understanding the role of ErbB4 in cancer is not only important for the treatment of tumors, but also for the treatment of other disorders in which ErbB4 plays a major role, e.g. cardiovascular disease.
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Affiliation(s)
- Vincent F M Segers
- Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium. .,Department of Cardiology, University Hospital Antwerp, Edegem, Belgium.
| | - Lindsey Dugaucquier
- Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Eline Feyen
- Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Hadis Shakeri
- Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium
| | - Gilles W De Keulenaer
- Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.,Department of Cardiology, ZNA Hospital, Antwerp, Belgium
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16
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Feng WW, Kurokawa M. Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3. [PMID: 32226926 PMCID: PMC7100881 DOI: 10.20517/cdr.2019.100] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.
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Affiliation(s)
- William W Feng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Manabu Kurokawa
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
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17
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Luhtala S, Staff S, Kallioniemi A, Tanner M, Isola J. Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4-1 and NRDP1, in primary breast cancer. BMC Cancer 2018; 18:1045. [PMID: 30367623 PMCID: PMC6204010 DOI: 10.1186/s12885-018-4917-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 10/08/2018] [Indexed: 12/17/2022] Open
Abstract
Background Human epidermal growth factor receptor HER3 (ErbB3), especially in association with its relative HER2 (ErbB2), is known as a key oncogene in breast tumour biology. Nonetheless, the prognostic relevance of HER3 remains controversial. NEDD4–1 and NRDP1 are signalling molecules closely related to the degradation of HER3 via ubiquitination. NEDD4–1 and NRDP1 have been reported to contribute to HER3-mediated signalling by regulating its localization and cell membrane retention. We studied correlations between HER3, NEDD4–1, and NRDP1 protein expression and their association with tumour histopathological characteristics and clinical outcomes. Methods The prevalence of immunohistochemically detectable expression profiles of HER3 (n = 177), NEDD4–1 (n = 145), and NRDP1 (n = 145) proteins was studied in primary breast carcinomas on archival formalin-fixed paraffin-embedded (FFPE) samples. Clinicopathological correlations were determined statistically using Pearson’s Chi-Square test. The Kaplan-Meier method, log-rank test (Mantel-Cox), and Cox regression analysis were utilized for survival analysis. Results HER3 protein was expressed in breast carcinomas without association with HER2 gene amplification status. Absence or low HER3 expression correlated with clinically aggressive features, such as triple-negative breast cancer (TNBC) phenotype, basal cell origin (cytokeratin 5/14 expression combined with ER negativity), large tumour size, and positive lymph node status. Low total HER3 expression was prognostic for shorter recurrence-free survival time in HER2-amplified breast cancer (p = 0.004, p = 0.020 in univariate and multivariate analyses, respectively). The majority (82.8%) of breast cancers demonstrated NEDD4–1 protein expression - while only a minor proportion (8.3%) of carcinomas expressed NRDP1. NEDD4–1 and NRDP1 expression were not associated with clinical outcomes in HER2-amplified breast cancer, irrespective of adjuvant trastuzumab therapy. Conclusions Low HER3 expression is suggested to be a valuable prognostic biomarker to predict recurrence in HER2-amplified breast cancer. Neither NEDD4–1 nor NRDP1 demonstrated relevance in prognostics or in the subclassification of HER2-amplified breast carcinomas. Electronic supplementary material The online version of this article (10.1186/s12885-018-4917-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Satu Luhtala
- BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Arvo Ylpön katu 34, 33520, Tampere, Finland.
| | - Synnöve Staff
- BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Arvo Ylpön katu 34, 33520, Tampere, Finland.,Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland
| | - Anne Kallioniemi
- BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Arvo Ylpön katu 34, 33520, Tampere, Finland
| | - Minna Tanner
- Department of Oncology, Tampere University Hospital, Tampere, Finland
| | - Jorma Isola
- BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Arvo Ylpön katu 34, 33520, Tampere, Finland
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18
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Shi J, Li F, Yao X, Mou T, Xu Z, Han Z, Chen S, Li W, Yu J, Qi X, Liu H, Li G. The HER4-YAP1 axis promotes trastuzumab resistance in HER2-positive gastric cancer by inducing epithelial and mesenchymal transition. Oncogene 2018; 37:3022-3038. [PMID: 29535422 PMCID: PMC5978807 DOI: 10.1038/s41388-018-0204-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 01/17/2018] [Accepted: 02/09/2018] [Indexed: 12/23/2022]
Abstract
Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab-treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer.
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Affiliation(s)
- Jiaolong Shi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Fengping Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Xingxing Yao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Tingyu Mou
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Zhijun Xu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Zheng Han
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Siyu Chen
- Department of Guangdong Laboratory Animals Monitoring Institute, Guangdong Key Laboratory of Laboratory Animals, Guangzhou, China
| | - Wende Li
- Department of Guangdong Laboratory Animals Monitoring Institute, Guangdong Key Laboratory of Laboratory Animals, Guangzhou, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Xiaolong Qi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, China.
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19
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Tan C, Hu W, He Y, Zhang Y, Zhang G, Xu Y, Tang J. Cytokine-mediated therapeutic resistance in breast cancer. Cytokine 2018; 108:151-159. [PMID: 29609137 DOI: 10.1016/j.cyto.2018.03.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 03/15/2018] [Accepted: 03/16/2018] [Indexed: 12/20/2022]
Abstract
Therapeutic resistance leading to tumor relapse is a major challenge in breast cancer (BCa) treatment. Numerous factors involved in multiple mechanisms promote the development of tumor chemo/radio-resistance. Cytokines/chemokines are important inflammatory factors and highly related to tumorigenesis, metastasis and tumors responses to treatment. A large number of studies have demonstrated that the network of cytokines activates multiple cell signaling pathways to promote tumor cell survival, proliferation, invasion, and migration. Particularly in BCa, cytokines-enhanced the epithelial-mesenchymal transition (EMT) process plays a pivotal role in the progression of metastatic phenotypes and resistance to the traditional chemo/radio-therapy. Virtually, therapeutic resistance is not entirely determined by tumor cell intrinsic characteristics but also dependent upon synchronized effects by numerous of local microenvironmental factors. Emerging evidence highlighted that exosomes secreted from various types of cells promote intercellular communication by transferring bioactive molecules including miRNAs and cytokines, suggesting that exosomes are essential for sustentation of tumor progression and therapeutic resistance within the tumor microenvironment. In this review, we discuss the mechanisms by which cytokines promote therapeutic resistance of BCa and suggest a potential approach for improving BCa therapeutics by inhibition of exosome function.
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Affiliation(s)
- Chunli Tan
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, PR China; Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, 42 Baiziting, Nanjing 210009, PR China
| | - Weizi Hu
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, PR China; Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, 42 Baiziting, Nanjing 210009, PR China
| | - Yunjie He
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China
| | - Yanyan Zhang
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, 42 Baiziting, Nanjing 210009, PR China
| | - Guangqin Zhang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, PR China
| | - Yong Xu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, 42 Baiziting, Nanjing 210009, PR China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, 101 Longmian Road, Nanjing 211166, PR China.
| | - Jinhai Tang
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, PR China.
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20
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Yun S, Koh J, Nam SK, Park JO, Lee SM, Lee K, Lee KS, Ahn SH, Park DJ, Kim HH, Choe G, Kim WH, Lee HS. Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients. Gastric Cancer 2018; 21:225-236. [PMID: 28573357 DOI: 10.1007/s10120-017-0732-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 05/25/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Neuregulin 1 (NRG1), a ligand for human epidermal growth factor (HER) 3 and HER4, can activates cell signaling pathways to promote carcinogenesis and metastasis. METHODS To investigate the clinicopathologic significance of NRG1 and its receptors, immunohistochemistry was performed for NRG1, HER3, and HER4 in 502 consecutive gastric cancers (GCs). Furthermore, HER2, microsatellite instability (MSI), and Epstein-Barr virus (EBV) status were investigated. NRG1 gene copy number (GCN) was determined by dual-color fluorescence in situ hybridization (FISH) in 388 available GCs. RESULTS NRG1 overexpression was observed in 141 (28.1%) GCs and closely correlated with HER3 (P = 0.034) and HER4 (P < 0.001) expression. NRG1 overexpression was significantly associated with aggressive features, including infiltrative tumor growth, lymphovascular, and neural invasion, high pathologic stage, and poor prognosis (all P < 0.05), but not associated with EBV, MSI, or HER2 status. Multivariate analysis identified NRG1 overexpression as an independent prognostic factor for survival (P = 0.040). HER3 and HER4 expressions were observed in 157 (31.3%) and 277 (55.2%), respectively. In contrast to NRG1, expression of these proteins was not associated with survival. NRG1 GCN gain (GCN ≥ 2.5) was detected in 14.7% patients, including two cases of amplification, and was moderately correlated with NRG1 overexpression (κ, 0.459; P < 0.001). CONCLUSIONS Although our results indicate a lack of prognostic significance of HER3 and HER4 overexpression in GC, overexpression of their ligand, NRG1, was associated with aggressive clinical features and represented an independent unfavorable prognostic factor. Therefore, NRG1 is a potential prognostic and therapeutic biomarker in GC patients.
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Affiliation(s)
- Sumi Yun
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.,Department of Diagnostic Pathology, Samkwang Medical Laboratories, Seoul, South Korea
| | - Jiwon Koh
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Soo Kyung Nam
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Jung Ok Park
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Sung Mi Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Kyoungyul Lee
- Department of Pathology, Kangwon National University Hospital, Chuncheon, Kangwon, South Korea
| | - Kyu Sang Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Gheeyoung Choe
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South Korea.
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21
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Nonagase Y, Yonesaka K, Kawakami H, Watanabe S, Haratani K, Takahama T, Takegawa N, Ueda H, Tanizaki J, Hayashi H, Yoshida T, Takeda M, Chiba Y, Tamura T, Nakagawa K, Tsurutani J. Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1. Oncotarget 2018; 7:84860-84871. [PMID: 27768588 PMCID: PMC5356704 DOI: 10.18632/oncotarget.12743] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 10/01/2016] [Indexed: 12/15/2022] Open
Abstract
Background Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
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Affiliation(s)
- Yoshikane Nonagase
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Kimio Yonesaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Satomi Watanabe
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Koji Haratani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Takayuki Takahama
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Naoki Takegawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Hiroto Ueda
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Junko Tanizaki
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Takeshi Yoshida
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Masayuki Takeda
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Takao Tamura
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
| | - Junji Tsurutani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan
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22
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Connell CM, Doherty GJ. Activating HER2 mutations as emerging targets in multiple solid cancers. ESMO Open 2017; 2:e000279. [PMID: 29209536 PMCID: PMC5708307 DOI: 10.1136/esmoopen-2017-000279] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/22/2017] [Accepted: 10/23/2017] [Indexed: 12/15/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases activates signalling pathways regulating cellular proliferation and survival. HER2 is a non-ligand-binding member of this family and exerts its activity through heterodimerisation with other EGFR family members. HER2 functional activation promotes oncogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 alterations. This has been best characterised in the context of HER2 gene amplification in breast and gastro-oesophageal cancers, for which HER2-directed drugs form part of standard treatment regimens. More recently, somatic HER2 gene mutations have been detected in a range of human cancer types. Preclinical data suggest that functionally activating HER2 mutations may drive and maintain cancers in a manner analogous to HER2 gene amplification and that HER2 mutations may similarly confer sensitivity to HER2-directed drugs. Here, we critically review the emerging roles for HER2-directed drugs in HER2 mutant cancers. We review data from experimental models, where our knowledge of the underlying biology of HER2 mutational activation remains incomplete. We discuss clinical data from Phase I and II clinical trials which evaluate HER2-directed agents (tyrosine kinase inhibitors and antibody-based drugs) in several cancer types. We highlight the heterogeneity of HER2 mutations in human cancers, differences in the clinical efficacy of HER2-directed drugs between cancer types and possible mechanisms of primary and acquired resistance, in order to guide clinical practice and future drug development.
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Affiliation(s)
- Claire M Connell
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
| | - Gary J Doherty
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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23
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Le Clorennec C, Bazin H, Dubreuil O, Larbouret C, Ogier C, Lazrek Y, Garambois V, Poul MA, Mondon P, Barret JM, Mathis G, Prost JF, Pèlegrin A, Chardès T. Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3. Mol Cancer Ther 2017; 16:1312-1323. [PMID: 28507002 DOI: 10.1158/1535-7163.mct-16-0886] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 03/16/2017] [Accepted: 04/18/2017] [Indexed: 11/16/2022]
Abstract
Exploratory clinical trials using therapeutic anti-HER3 antibodies strongly suggest that neuregulin (NRG1; HER3 ligand) expression at tumor sites is a predictive biomarker of anti-HER3 antibody efficacy in cancer. We hypothesized that in NRG1-expressing tumors, where the ligand is present before antibody treatment, anti-HER3 antibodies that do not compete with NRG1 for receptor binding have a higher receptor-neutralizing action than antibodies competing with the ligand for binding to HER3. Using time-resolved-fluorescence energy transfer (TR-FRET), we demonstrated that in the presence of recombinant NRG1, binding of 9F7-F11 (a nonligand-competing anti-HER3 antibody) to HER3 is increased, whereas that of ligand-competing anti-HER3 antibodies (H4B-121, U3-1287, Ab#6, Mab205.10.2, and MOR09825) is decreased. Moreover, 9F7-F11 showed higher efficacy than antibodies that compete with the ligand for binding to HER3. Specifically, 9F7-F11 inhibition of cell proliferation and of HER3/AKT/ERK1/2 phosphorylation as well as 9F7-F11-dependent cell-mediated cytotoxicity were higher in cancer cells preincubated with recombinant NRG1 compared with cells directly exposed to the anti-HER3 antibody. This translated in vivo into enhanced growth inhibition of NRG1-expressing BxPC3 pancreatic, A549 lung, and HCC-1806 breast cell tumor xenografts in mice treated with 9F7-F11 compared with H4B-121. Conversely, both antibodies had similar antitumor effect in NRG1-negative HPAC pancreatic carcinoma cells. In conclusion, the allosteric modulator 9F7-F11 shows increased anticancer effectiveness in the presence of NRG1 and thus represents a novel treatment strategy for NRG1-addicted tumors. Mol Cancer Ther; 16(7); 1312-23. ©2017 AACR.
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Affiliation(s)
- Christophe Le Clorennec
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | | | | | - Christel Larbouret
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | - Charline Ogier
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | - Yassamine Lazrek
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | - Véronique Garambois
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | - Marie-Alix Poul
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | | | | | | | | | - André Pèlegrin
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
| | - Thierry Chardès
- IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. .,INSERM U1194, Montpellier, France.,Université de Montpellier, Montpellier, France.,ICM, Institut régional du Cancer de Montpellier, France
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24
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Shi H, Zhang W, Zhi Q, Jiang M. Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms. Tumour Biol 2016; 37:15411–15431. [PMID: 27726101 DOI: 10.1007/s13277-016-5467-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 09/23/2016] [Indexed: 12/12/2022] Open
Abstract
In the era of new and mostly effective molecular targeted therapies, human epidermal growth factor receptor 2 positive (HER2+) cancers are still intractable diseases. Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor, has greatly improved breast cancer prognosis in recent years after the initial introduction of trastuzumab (Herceptin). However, clinical evidence indicates the existence of both primary unresponsiveness and secondary lapatinib resistance, which leads to the failure of this agent in HER2+ cancer patients. It remains a major clinical challenge to target the oncogenic pathways with drugs having low resistance. Multiple pathways are involved in the occurrence of lapatinib resistance, including the pathways of receptor tyrosine kinase, non-receptor tyrosine kinase, autophagy, apoptosis, microRNA, cancer stem cell, tumor metabolism, cell cycle, and heat shock protein. Moreover, understanding the relationship among these mechanisms may contribute to future tumor combination therapies. Therefore, it is of urgent necessity to elucidate the precise mechanisms of lapatinib resistance and improve the therapeutic use of this agent in clinic. The present review, in the hope of providing further scientific support for molecular targeted therapies in HER2+ cancers, discusses about the latest findings and new concepts on molecular mechanisms underlying lapatinib resistance.
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Affiliation(s)
- Huiping Shi
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, China
| | - Weili Zhang
- Department of Gastroenterology, Xiangcheng People's Hospital, Suzhou, Jiangsu Province, 215131, China
| | - Qiaoming Zhi
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, China.
| | - Min Jiang
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215006, China.
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25
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Duchnowska R, Wysocki PJ, Korski K, Czartoryska-Arłukowicz B, Niwińska A, Orlikowska M, Radecka B, Studziński M, Demlova R, Ziółkowska B, Merdalska M, Hajac Ł, Myśliwiec P, Zuziak D, Dębska-Szmich S, Lang I, Foszczyńska-Kłoda M, Karczmarek-Borowska B, Żawrocki A, Kowalczyk A, Biernat W, Jassem J. Immunohistochemical prediction of lapatinib efficacy in advanced HER2-positive breast cancer patients. Oncotarget 2016; 7:550-64. [PMID: 26623720 PMCID: PMC4808017 DOI: 10.18632/oncotarget.6375] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 11/13/2015] [Indexed: 12/22/2022] Open
Abstract
Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25–0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06–3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13–2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29–6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43–0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48–7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25–7.58; p = 0.015). In conclusion: the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways – AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.
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Affiliation(s)
| | | | | | | | - Anna Niwińska
- The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
| | | | | | | | | | | | | | | | | | | | | | - Istvan Lang
- Department of Medical Oncology, National Institute of Oncology, Budapest, Hungary
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26
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Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α. Mol Cell Biol 2016; 36:2011-26. [PMID: 27185877 DOI: 10.1128/mcb.00180-16] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/06/2016] [Indexed: 01/11/2023] Open
Abstract
The growth factor heregulin (HRG), a ligand of ErbB3 and ErbB4 receptors, contributes to breast cancer development and the promotion of metastatic disease, and its expression in breast tumors has been associated with poor clinical outcome and resistance to therapy. In this study, we found that breast cancer cells exposed to sustained HRG treatment show markedly enhanced Rac1 activation and migratory activity in response to the CXCR4 ligand SDF-1/CXCL12, effects mediated by P-Rex1, a Rac-guanine nucleotide exchange factor (GEF) aberrantly expressed in breast cancer. Notably, HRG treatment upregulates surface expression levels of CXCR4, a G protein-coupled receptor (GPCR) implicated in breast cancer metastasis and an indicator of poor prognosis in breast cancer patients. A detailed mechanistic analysis revealed that CXCR4 upregulation and sensitization of the Rac response/motility by HRG are mediated by the transcription factor hypoxia-inducible factor 1α (HIF-1α) via ErbB3 and independently of ErbB4. HRG caused prominent induction in the nuclear expression of HIF-1α, which transcriptionally activates the CXCR4 gene via binding to a responsive element located in positions -1376 to -1372 in the CXCR4 promoter, as revealed by mutagenesis analysis and chromatin immunoprecipitation (ChIP). Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1α-mediated transcriptional induction of CXCR4.
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27
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McCabe Pryor M, Steinkamp MP, Halasz AM, Chen Y, Yang S, Smith MS, Zahoransky-Kohalmi G, Swift M, Xu XP, Hanein D, Volkmann N, Lidke DS, Edwards JS, Wilson BS. Orchestration of ErbB3 signaling through heterointeractions and homointeractions. Mol Biol Cell 2015; 26:4109-23. [PMID: 26378253 PMCID: PMC4710241 DOI: 10.1091/mbc.e14-06-1114] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Accepted: 09/09/2015] [Indexed: 12/27/2022] Open
Abstract
Members of the ErbB family of receptor tyrosine kinases are capable of both homointeractions and heterointeractions. Because each receptor has a unique set of binding sites for downstream signaling partners and differential catalytic activity, subtle shifts in their combinatorial interplay may have a large effect on signaling outcomes. The overexpression and mutation of ErbB family members are common in numerous human cancers and shift the balance of activation within the signaling network. Here we report the development of a spatial stochastic model that addresses the dynamics of ErbB3 homodimerization and heterodimerization with ErbB2. The model is based on experimental measures for diffusion, dimer off-rates, kinase activity, and dephosphorylation. We also report computational analysis of ErbB3 mutations, generating the prediction that activating mutations in the intracellular and extracellular domains may be subdivided into classes with distinct underlying mechanisms. We show experimental evidence for an ErbB3 gain-of-function point mutation located in the C-lobe asymmetric dimerization interface, which shows enhanced phosphorylation at low ligand dose associated with increased kinase activity.
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Affiliation(s)
- Meghan McCabe Pryor
- Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131 Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545
| | - Mara P Steinkamp
- Department of Pathology, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131
| | - Adam M Halasz
- Department of Mathematics, West Virginia University, Morgantown, WV 25606
| | - Ye Chen
- Department of Mathematics, West Virginia University, Morgantown, WV 25606
| | - Shujie Yang
- Department of OB/GYN, University of Iowa Carver College of Medicine, Iowa City, IA 52242
| | | | | | - Mark Swift
- Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037
| | - Xiao-Ping Xu
- Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037
| | - Dorit Hanein
- Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037
| | - Niels Volkmann
- Bioinformatics and Systems Biology Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037
| | - Diane S Lidke
- Department of Pathology, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131
| | - Jeremy S Edwards
- Department of Chemical and Biological Engineering, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131 Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM 87131
| | - Bridget S Wilson
- Department of Pathology, University of New Mexico, Albuquerque, NM 87131 Cancer Center, University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131
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Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev 2015; 41:877-83. [PMID: 26276735 DOI: 10.1016/j.ctrv.2015.08.001] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 07/30/2015] [Accepted: 08/03/2015] [Indexed: 12/19/2022]
Abstract
Targeted therapies have been approved for various malignancies but the acquisition of resistance remains a substantial challenge in the clinical management of advanced cancers. Twenty-five per cent of breast cancers overexpress ErbB2/HER2, which confers a more aggressive phenotype and is associated with a poor prognosis. HER2-targeting therapies (trastuzumab, pertuzumab, TDM1 and lapatinib) are available, but a significant fraction of HER2-positive breast cancers eventually relapse or progress. This suggests that acquired or intrinsic resistance enables escape from HER2 inhibition. This review focuses on mechanisms of intrinsic/acquired resistance to lapatinib identified in preclinical and clinical studies. A better understanding of these mechanisms could lead to novel predictive markers of lapatinib response and to novel therapeutic strategies for breast cancer patients.
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Dey N, Williams C, Leyland-Jones B, De P. A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK. Am J Transl Res 2015; 7:733-750. [PMID: 26064441 PMCID: PMC4455348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 04/11/2015] [Indexed: 06/04/2023]
Abstract
ERBB3/HER3 is the most intriguing RTK by virtue of its ability to transduce multiple cytosolic signals for the proliferation and growth of tumor cells in spite of being a "kinase dead" receptor that binds to its true ligand, heregulin. Although other members of the HER3 family like EGFR and HER2 have long been recognized to be associated with breast tumorigenesis and studied because of their predictive and prognostic value, the significance of HER3 as an irrefutable component of HER family signalosome is a relatively new development. The recent understanding of signals originating from the oncogenic partnership of HER3 with HER2 in the context of HER2 amplification/overexpression showed the critical clinical value for the treatment of HER2+BC. The downstream signaling cascade (included but not limited to the PI3K signaling) associated with signals originating from HER2:HER3 dimers play a vital role in the tumorigenesis, drug-resistance and tumor progression of HER2+BC. The upregulation of HER3 activity provides an alternate "escape route" via which tumor cells bypass either the inhibition of the HER family RTKs or the inhibition of the downstream PI3K-AKT-mTOR signaling pathway. By understanding the signaling that provides this "escape route" for these tumor cells treated with a targeted therapy (HER2 inhibitors or inhibitors of downstream PI3K-AKT-mTOR signaling pathway), we are just beginning to appreciate the prognostic value of HER3 in breast cancer. In this review, we will discuss the relevance of HER3 signaling in the context of, (1) downstream oncogenic signals and (2) therapeutic options in HER2 amplified BC.
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Affiliation(s)
- Nandini Dey
- Department of Molecular and Experimental Medicine, Avera Cancer InstituteSioux Falls, SD
- Department of Internal Medicine, SSOM, University of South DakotaSD
| | - Casey Williams
- Department of Molecular and Experimental Medicine, Avera Cancer InstituteSioux Falls, SD
- Department of Internal Medicine, SSOM, University of South DakotaSD
| | - Brain Leyland-Jones
- Department of Molecular and Experimental Medicine, Avera Cancer InstituteSioux Falls, SD
- Department of Internal Medicine, SSOM, University of South DakotaSD
| | - Pradip De
- Department of Molecular and Experimental Medicine, Avera Cancer InstituteSioux Falls, SD
- Department of Internal Medicine, SSOM, University of South DakotaSD
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30
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Mendell J, Freeman DJ, Feng W, Hettmann T, Schneider M, Blum S, Ruhe J, Bange J, Nakamaru K, Chen S, Tsuchihashi Z, von Pawel J, Copigneaux C, Beckman RA. Clinical Translation and Validation of a Predictive Biomarker for Patritumab, an Anti-human Epidermal Growth Factor Receptor 3 (HER3) Monoclonal Antibody, in Patients With Advanced Non-small Cell Lung Cancer. EBioMedicine 2015; 2:264-71. [PMID: 26137564 PMCID: PMC4484825 DOI: 10.1016/j.ebiom.2015.02.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 02/10/2015] [Accepted: 02/11/2015] [Indexed: 12/15/2022] Open
Abstract
Background During early clinical development, prospective identification of a predictive biomarker and validation of an assay method may not always be feasible. Dichotomizing a continuous biomarker measure to classify responders also leads to challenges. We present a case study of a prospective–retrospective approach for a continuous biomarker identified after patient enrollment but defined prospectively before the unblinding of data. An analysis of the strengths and weaknesses of this approach and the challenges encountered in its practical application are also provided. Methods HERALD (NCT02134015) was a double-blind, phase 2 study in patients with non-small cell lung cancer (NSCLC) randomized to erlotinib with placebo or with high or low doses of patritumab, a monoclonal antibody targeted against human epidermal growth factor receptor 3 (HER3). While the primary objective was to assess safety and progression-free survival (PFS), a secondary objective was to determine a single predictive biomarker hypothesis to identify subjects most likely to benefit from the addition of patritumab. Although not identified as the primary biomarker in the study protocol, on the basis of preclinical results from 2 independent laboratories, expression levels of the HER3 ligand heregulin (HRG) were prospectively declared the predictive biomarker before data unblinding but after subject enrollment. An assay to measure HRG mRNA was developed and validated. Other biomarkers, such as epidermal growth factor receptor (EGFR) mutation status, were also evaluated in an exploratory fashion. The cutoff value for high vs. low HRG mRNA levels was set at the median delta threshold cycle. A maximum likelihood analysis was performed to evaluate the provisional cutoff. The relationship of HRG values to PFS hazard ratios (HRs) was assessed as a measure of internal validation. Additional NSCLC samples were analyzed to characterize HRG mRNA distribution. Results The subgroup of patients with high HRG mRNA levels (“HRG-high”) demonstrated clinical benefit from patritumab treatment with HRs of 0.37 (P = 0.0283) and 0.29 (P = 0.0027) in the high- and low-dose patritumab arms, respectively. However, only 102 of the 215 randomized patients (47.4%) had sufficient tumor samples for HRG mRNA measurement. Maximum likelihood analysis showed that the provisional cutoff was within the optimal range. In the placebo arm, the HRG-high subgroup demonstrated worse prognosis compared with HRG-low. A continuous relationship was observed between increased HRG mRNA levels and lower HR. Additional NSCLC samples (N = 300) demonstrated a similar unimodal distribution to that observed in this study, suggesting that the defined cutoff may be applicable to future NSCLC studies. Conclusions The prospective–retrospective approach was successful in clinically validating a probable predictive biomarker. Post hoc in vitro studies and statistical analyses permitted further testing of the underlying assumptions. However, limitations of this analysis include the incomplete collection of adequate tumor tissue and a lack of stratification. In a phase 3 study, findings are being confirmed, and the HRG cutoff value is being further refined. ClinicalTrials.gov Number NCT02134015.
High heregulin levels predict benefit from patritumab treatment in patients with NSCLC. A prospective–retrospective approach provisionally validated a predictive biomarker. Post hoc analyses can be used to test underlying assumptions in biomarker validation. The median may be a reasonable initial cutoff for a unimodal continuous biomarker.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal/administration & dosage
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Antibodies, Neutralizing/administration & dosage
- Antibodies, Neutralizing/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Broadly Neutralizing Antibodies
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/mortality
- Disease-Free Survival
- Double-Blind Method
- ErbB Receptors/genetics
- Erlotinib Hydrochloride/administration & dosage
- Erlotinib Hydrochloride/therapeutic use
- Female
- Humans
- Lung Neoplasms/drug therapy
- Lung Neoplasms/mortality
- Male
- Middle Aged
- Neuregulin-1/blood
- Neuregulin-1/genetics
- Prospective Studies
- Receptor, ErbB-3/blood
- Receptor, ErbB-3/immunology
- Retrospective Studies
- Translational Research, Biomedical
- Treatment Outcome
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Affiliation(s)
- Jeanne Mendell
- Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA
- Corresponding author.
| | - Daniel J. Freeman
- Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA
| | - Wenqin Feng
- Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA
| | - Thore Hettmann
- U3 Pharma GmbH, Fraunhoferstraße 22, 82152 Martinsried, Germany
| | | | - Sabine Blum
- U3 Pharma GmbH, Fraunhoferstraße 22, 82152 Martinsried, Germany
| | - Jens Ruhe
- U3 Pharma GmbH, Fraunhoferstraße 22, 82152 Martinsried, Germany
| | - Johannes Bange
- U3 Pharma GmbH, Fraunhoferstraße 22, 82152 Martinsried, Germany
| | - Kenji Nakamaru
- Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
| | - Shuquan Chen
- Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA
| | | | - Joachim von Pawel
- Asklepios Fachkliniken, München Gauting, Robert-Koch-Allee 2, 82131 Gauting, Germany
| | | | - Robert A. Beckman
- Daiichi Sankyo Pharma Development, 399 Thornall St, Edison, NJ 08837, USA
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31
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Matsuoka T, Yashiro M. Recent advances in the HER2 targeted therapy of gastric cancer. World J Clin Cases 2015; 3:42-51. [PMID: 25610849 PMCID: PMC4295218 DOI: 10.12998/wjcc.v3.i1.42] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 10/09/2014] [Accepted: 11/19/2014] [Indexed: 02/05/2023] Open
Abstract
Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2 (HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancer-resistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.
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32
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HER2 expression in primary gastric cancers and paired synchronous lymph node and liver metastases. A possible road to target HER2 with radionuclides. Tumour Biol 2014; 35:6319-26. [PMID: 24643685 DOI: 10.1007/s13277-014-1830-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 03/05/2014] [Indexed: 12/14/2022] Open
Abstract
Resistance has been reported to human epidermal growth factor receptor 2 (HER2)-targeted therapy with the tyrosine kinase inhibitor lapatinib and the antibody trastuzumab in metastatic gastric cancer. An alternative or complement might be to target the extracellular domain of HER2 with therapy-effective radionuclides. The fraction of patients with HER2 expression in primary tumors and major metastatic sites, e.g., lymph nodes and liver, was analyzed to evaluate the potential for such therapy. Samples from primary tumors and lymph node and liver metastases were taken from each patient within a few hours, and to our knowledge, such sampling is unique. The number of analyzed cases was therefore limited, since patients that had received preoperative radiotherapy, chemotherapy, or HER2-targeted therapy were excluded. From a large number of considered patients, only 29 could be included for HER2 analysis. Intracellular mutations were not analyzed since they are assumed to have no or minor effect on the extracellular binding of molecules that deliver radionuclides. HER2 was positive in nearly 52 % of the primary tumors, and these expressed HER2 in corresponding lymph node and liver metastases in 93 and 100 % of the cases, respectively. Similar values for primary tumors and also good concordance with metastases have been indicated in the literature. Thus, relevant radionuclides and targeting molecules for nuclear medicine-based noninvasive, whole-body receptor analysis, dose planning, and therapy can be applied for many patients; see "Discussion" Hopefully, more patients can then be treated with curative instead of palliative intention.
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Kang JC, Poovassery JS, Bansal P, You S, Manjarres IM, Ober RJ, Ward ES. Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells. MAbs 2013; 6:340-53. [PMID: 24492289 PMCID: PMC3984324 DOI: 10.4161/mabs.27658] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The use of antibodies in therapy and diagnosis has undergone an unprecedented expansion during the past two decades. This is due in part to innovations in antibody engineering that now offer opportunities for the production of “second generation” antibodies with multiple specificities or altered valencies. The targeting of individual components of the human epidermal growth factor receptor (HER)3-PI3K signaling axis, including the preferred heterodimerization partner HER2, is known to have limited anti-tumor effects. The efficacy of antibodies or small molecule tyrosine kinase inhibitors (TKIs) in targeting this axis is further reduced by the presence of the HER3 ligand, heregulin. To address these shortcomings, we performed a comparative analysis of two distinct approaches toward reducing the proliferation and signaling in HER2 overexpressing tumor cells in the presence of heregulin. These strategies both involve the use of engineered antibodies in combination with the epidermal growth factor receptor (EGFR)/HER2 specific TKI, lapatinib. In the first approach, we generated a bispecific anti-HER2/HER3 antibody that, in the presence of lapatinib, is designed to sequester HER3 into inactive HER2-HER3 dimers that restrain HER3 interactions with other possible dimerization partners. The second approach involves the use of a tetravalent anti-HER3 antibody with the goal of inducing efficient HER3 internalization and degradation. In combination with lapatinib, we demonstrate that although the multivalent HER3 antibody is more effective than its bivalent counterpart in reducing heregulin-mediated signaling and growth, the bispecific HER2/HER3 antibody has increased inhibitory activity. Collectively, these observations provide support for the therapeutic use of bispecifics in combination with TKIs to recruit HER3 into complexes that are functionally inert.
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Affiliation(s)
- Jeffrey C Kang
- Department of Biomedical Engineering; University of Texas at Dallas; Richardson, TX USA; Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Jayakumar S Poovassery
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX USA
| | - Pankaj Bansal
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA
| | - Sungyong You
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX USA
| | - Isabel M Manjarres
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX USA
| | - Raimund J Ober
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA; Department of Electrical Engineering; University of Texas at Dallas; Richardson, TX USA
| | - E Sally Ward
- Department of Immunology; University of Texas Southwestern Medical Center; Dallas, TX USA
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Sato Y, Yashiro M, Takakura N. Heregulin induces resistance to lapatinib-mediated growth inhibition of HER2-amplified cancer cells. Cancer Sci 2013; 104:1618-25. [PMID: 24112719 PMCID: PMC7653524 DOI: 10.1111/cas.12290] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Revised: 09/11/2013] [Accepted: 09/19/2013] [Indexed: 12/17/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 20% of gastric and gastroesophageal junction cancers in the United States and European Union. Lapatinib, a dual HER2 and epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated clinical efficacy in HER2-amplified cancer cells. However, several studies have shown that some cytokines can mediate resistance to lapatinib using their receptor tyrosine kinase (RTK) pathways. One of these, Heregulin1 (HRG1), can confer resistance to lapatinib-mediated growth inhibition in HER2-amplified breast cancer cells, but the underlying mechanisms remain unknown. Here, we investigated whether and how HRG1 causes resistance to lapatinib in gastric and gastroesophageal junction cancers in vitro. HER2-amplified gastric and gastroesophageal junction cancer cell lines were highly sensitive to lapatinib. Exposure to HRG1 together with lapatinib rescued cells from lapatinib-induced cell cycle arrest and apoptosis. Downregulation of HER3 with siRNA in the presence of HRG1 re-sensitized HER2-amplified cancer cells to lapatinib. Immunoblotting analysis indicated that HRG1 re-activated HER3 and AKT in the presence of lapatinib, which persisted for at least 72 h. Activation of HER3 and downstream AKT was mediated by residual activity of HER2. HRG1-mediated resistance could be reduced by PI3K/mTOR inhibitors or by complete inhibition of HER2. Thus, we conclude that HRG1 mediates resistance to lapatinib through HER3 and AKT activation, and that this depends on residual HER2 activity. Lapatinib in combination with anti-PI3K therapies or more potent HER2 inhibitors would improve the efficacy and avoid the emergence of resistant cells.
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Affiliation(s)
- Yuji Sato
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan; Medicinal Research Laboratories, Shionogi Pharmaceutical, Toyonaka, Osaka, Japan
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