Molecular mechanisms of resistance to HER2 inhibitors in breast cancer

乳腺癌HER2抑制剂耐药的分子机制

• 批准号: 8138650
• 负责人: BRENT N REXER
• 金额: $ 16.31万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138650
• 关键词: Advanced Malignant Neoplasm; Aftercare; Antibodies; Basic Research Breast Cancer; Basic Science; Binding; Biological Models; Breast; Breast Cancer Cell; Cancer Biology; Cancer Research Project; Catalytic Domain; Cell Line; Cells; Clinical; Clinical Trials; Commit; Coupled; Data; Development; Development Plans; Drug resistance; ERBB2 gene; ERBB3 gene; Effectiveness; Environment; Epidermal Growth Factor Receptor; ErbB Receptor Family Protein; FDA approved; Faculty; Fellowship; Fostering; Gene Amplification; HER2 inhibition; Hematology; Human; Immunoprecipitation; Internal Medicine; Investigation; Malignant Neoplasms; Mass Spectrum Analysis; Mentors; Modeling; Molecular; Monoclonal Antibodies; Mutation; Oncogenes; Outcome; PIK3CA gene; PTEN gene; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Physicians; Protein Isoforms; Proteins; Public Health; RNA Interference; Receptor Protein-Tyrosine Kinases; Relapse; Research; Research Training; Residencies; Resistance; Resistance development; Resources; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Testing; Therapeutic; Training; Translational Research; Trastuzumab; Tyrosine Kinase Inhibitor; Up-Regulation; Work; Xenograft procedure; anticancer research; clinical practice; effective therapy; graduate student; improved; in vivo; inhibitor/antagonist; lapatinib; malignant breast neoplasm; member; mouse model; mutant; oncology; outcome forecast; overexpression; pressure; prevent; programs; public health relevance; receptor; research study; resistance mechanism; response; small molecule; therapeutic target; tumor

DESCRIPTION (provided by applicant): This proposal describes a five year training plan for the development of an independent translational academic cancer research program. The candidate has had research training as a graduate student and residency training in internal medicine, has completing fellowship training in hematology/oncology, and continues as faculty in a mentored research environment. The proposed program will promote the candidate's further training in advanced cancer biology, mouse models of cancer, and translational breast cancer research. The candidate's mentor is a recognized leader in breast cancer basic science and translational research, and is committed to supervising the PI's research training and fostering his transition to independence. Training will occur in an environment of active clinical practice and basic science investigation in breast cancer, coupled with outstanding resources for the proposed research and with institutional support for the nurturing and development of physician-scientists. The proposed research will focus on understanding molecular mechanisms of resistance to HER2 inhibitors in breast cancer. Amplification of the HER2 oncogene occurs in 25% of human breast cancers. Trastuzumab, an antibody against HER2, and lapatinib, a tyrosine kinase inhibitor of HER2 and EGFR, are effective therapies for patients with HER2+ breast cancer, but most patients treated with these agents eventually relapse, suggesting that tumors acquire or intrinsically possess mechanisms for escape from HER2 inhibition. Aberrant activation of the phosphoinositide-3-kinase (PI3K)-Akt axis is emerging as an important mechanism of resistance to anti-HER2 therapies, supported by preliminary data from cell line model systems of lapatinib resistance. We hypothesize that as a result of the selective pressure of treatment, resistance to HER2 inhibition results from reactivation of the PI3K-Akt axis through upregulation of alternate compensatory signaling and/or mutations in the PI3K pathway. Inhibition of these alternate pathways should provide therapeutic targets to prevent or overcome resistance to anti-HER2 treatment. Specific aims are 1) To determine the molecular mechanisms of aberrant PI3K-Akt activation in lapatinib-resistant HER2-overexpressing breast cancer cells; 2) To determine the mechanisms whereby PI3K mutations contribute to PI3K-Akt pathway activation in drug-resistant cells; and 3) To determine whether therapeutic inhibitors of PI3K restore sensitivity to HER2 inhibitors and whether PI3K pathway activation predicts clinical response to HER2 inhibitors. Experiments in Aim 1 will use cell line models of lapatinib resistance to determine the role of HER3 in activating PI3K, or to identify other candidate activators of the PI3K pathway. Several approaches including RNAi knockdown of candidate proteins, immunoprecipitation of PI3K subunits to identify binding partners, and pharmacologic manipulation of suspected resistance pathways will be tested. Aim 2 will focus on understanding the role of PI3K mutations by using mass spectrometry to quantitate mutant PI3K isoforms in resistant cells, and by knockdown of PI3K subunits to test the role of mutations on PI3K signaling. Using xenograft mouse models, Aim 3 will test whether PI3K mutations confer resistance in vivo, and whether combination of PI3K inhibition with HER2 inhbitors provides a strategy to overcome HER2 inhibitor resistance. Further, the hypothesis that activation of the PI3K pathway by PIK3CA mutation or PTEN loss predicts for clinical resistance to HER2 inhibitors will be tested in tumor samples from a neoajuvant clinical trial of lapatinib. PUBLIC HEALTH RELEVANCE: Treatment of HER2-positive breast cancer with targeted therapies has been successful, but despite the effectiveness of these therapies, most patients eventually progress after treatment. This research will focus on understanding how tumors develop resistance to HER2-directed therapies. This work will also test potential strategies for overcoming that resistance, to benefit public health by improving the outcome of patients with HER2-positive breast cancer.

描述（由申请人提供）：该提案描述了一个独立的转化学术癌症研究项目发展的五年培训计划。该候选人已接受过研究生研究培训和内科住院医师培训，已完成血液学/肿瘤学的奖学金培训，并在有指导的研究环境中继续担任教师。该计划将促进候选人在高级癌症生物学，癌症小鼠模型和转化乳腺癌研究方面的进一步培训。候选人的导师是乳腺癌基础科学和转化研究领域公认的领导者，并致力于监督PI的研究培训并促进其向独立过渡。培训将在积极的临床实践和乳腺癌基础科学研究的环境中进行，同时为拟议的研究提供优秀的资源，并为培养和发展医师科学家提供机构支持。