Overcoming Resistance Mechanisms to Anaplastic Lymphoma Kinase Inhibitors

克服间变性淋巴瘤激酶抑制剂的耐药机制

• 批准号: 10734260
• 负责人: Aaron N Hata
• 金额: $ 41.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734260
• 关键词: ALK gene; Accounting; Address; Adoptive Cell Transfers; Alleles; Automobile Driving; Biopsy; Bypass; Cancer Etiology; Cancer Patient; Cell Line; Cessation of life; Chimeric Proteins; Chromosomal Rearrangement; Clinic; Clinical; Clinical Trials; Collection; Combined Modality Therapy; Data; Development; Diagnosis; Disease; Drug resistance; EP300 gene; Engineering; Epigenetic Process; Epitopes; Foundations; Future; Gene Fusion; Gene Rearrangement; Generations; Genetic Transcription; Genomics; Goals; IL2-Inducible T-Cell Kinase; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Institution; Institutional Review Boards; MHC Class I Genes; Malignant neoplasm of lung; Maps; Mediating; Methods; Mutation; Neurons; New Agents; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oncogenic; Outcome; Patients; Pattern; Phosphotransferases; Pre-Clinical Model; Protocols documentation; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recurrence; Recurrent disease; Research; Research Personnel; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Transcription Coactivator; Tumor Cell Line; Tyrosine Kinase Inhibitor; United States; acquired drug resistance; anaplastic lymphoma kinase; cohort; crizotinib; immunogenic; improved; in vivo; inhibitor; kinase inhibitor; molecular subtypes; mortality; neoantigens; next generation; non-genomic; novel; novel strategies; novel therapeutic intervention; pharmacologic; programs; rational design; resistance mechanism; resistance mutation; standard care; standard of care; therapeutic target; therapy development; tumor

Project Summary Non-small cell lung cancers (NSCLC) harboring oncogenic anaplastic lymphoma kinase (ALK) gene rearrangements (i.e., ‘ALK+’) comprise a distinct molecular subset of lung cancer with marked sensitivity to ALK tyrosine kinase inhibitors (TKIs). While ALK TKIs are initially highly effective, acquired drug resistance remains a fundamental challenge that limits clinical benefit and causes disease relapse in most patients. We and others have characterized mechanisms of resistance, in particular so-called “on-target” resistance mediated by secondary acquired ALK kinase domain mutations that can be overcome with more potent next-generation (2nd- or 3rd-generation) inhibitors. In recent years, the standard treatment paradigm for patients diagnosed with advanced ALK+ lung cancers has shifted from sequential therapy using the 1st-generation ALK TKI crizotinib followed by next-generation TKIs, to initial therapy using a next-generation ALK TKI upfront. Our preliminary data indicate that off-target (i.e., ALK-independent) resistance mechanisms are prevalent following next-generation ALK TKIs. Yet, the spectrum of off-target resistance mechanisms and strategies to overcome these remain poorly understood, presenting a barrier to the development of treatment options for these patients. The overarching objective of the proposed research is to identify and develop complementary, mechanism-informed and mechanism-agnostic approaches for overcoming off-target resistance to next-generation ALK TKIs. We will use comprehensive genomic and non-genomic assessment of an expanded cohort of patient tumor specimens to determine the clinical spectrum of off-target resistance mechanisms after first-line use of next-generation ALK TKIs, and we will develop new methods for identifying patients with bypass-mediated resistance most likely to benefit from rationally designed combination therapies. Using ALK TKI-resistant tumor cell lines derived from patient biopsies, we will screen for epigenetic mechanisms that drive resistance independent of canonical bypass signaling pathways, with initial studies focused on defining the role of the transcriptional co-activator p300/CBP as a novel driver of off-target ALK TKI resistance and therapeutic target. These efforts will enable patient-specific, mechanism-informed therapeutic strategies. In parallel, we will develop a mechanism-agnostic approach that leverages ALK as a tumor-specific “neoantigen” whose expression is maintained in resistant tumors. Using T cell-based functional screens, we will identify ALK-reactive T cell receptors (TCRs) that are capable of recognizing resistant ALK+ NSCLCs. This will provide the foundation for engineering ALK TCR adoptive cellular therapy as a TKI-orthogonal, immune-based approach for overcoming resistance. Collectively, the proposed studies will provide a comprehensive understanding of resistance to next-generation ALK TKIs and pave the way for the development of new therapeutic strategies that can effectively overcome most of off-target resistance in the clinic, ultimately improving and prolonging the lives of patients with advanced ALK+ lung cancers.

项目总结

项目成果

Ceritinib in ALK-rearranged non-small-cell lung cancer.

• DOI: 10.1056/nejmoa1311107
• 发表时间: 2014-03-27
• 期刊: The New England journal of medicine
• 作者: Shaw AT;Kim DW;Mehra R;Tan DS;Felip E;Chow LQ;Camidge DR;Vansteenkiste J;Sharma S;De Pas T;Riely GJ;Solomon BJ;Wolf J;Thomas M;Schuler M;Liu G;Santoro A;Lau YY;Goldwasser M;Boral AL;Engelman JA
• 通讯作者: Engelman JA

Recent Advances in Targeting ROS1 in Lung Cancer.

• DOI: 10.1016/j.jtho.2017.08.002
• 发表时间: 2017-11
• 期刊: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
• 作者: Lin JJ;Shaw AT
• 通讯作者: Shaw AT

Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

通过循环肿瘤DNA的纵向分析来跟踪对碱酪氨酸激酶抑制剂的耐药性的演变。

• DOI: 10.1200/po.17.00160
• 发表时间: 2018
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Dagogo-Jack I;Brannon AR;Ferris LA;Campbell CD;Lin JJ;Schultz KR;Ackil J;Stevens S;Dardaei L;Yoda S;Hubbeling H;Digumarthy SR;Riester M;Hata AN;Sequist LV;Lennes IT;Iafrate AJ;Heist RS;Azzoli CG;Farago AF;Engelman JA;Lennerz JK;Benes CH;Leary RJ;Shaw AT;Gainor JF
• 通讯作者: Gainor JF

Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.

• DOI: 10.1038/s41698-023-00464-y
• 发表时间: 2023-11-03
• 期刊: NPJ precision oncology
• 影响因子: 7.9

Efficacy and Tolerability of ALK/MET Combinations in Patients With ALK-Rearranged Lung Cancer With Acquired MET Amplification: A Retrospective Analysis.

• DOI: 10.1016/j.jtocrr.2023.100534
• 发表时间: 2023-08
• 期刊: JTO CLINICAL AND RESEARCH REPORTS
• 作者: Dagogo-Jack, Ibiayi;Kiedrowski, Lesli A.;Heist, Rebecca S.;Lin, Jessica J.;Meador, Catherine B.;Krueger, Elizabeth A.;Do, Andrew;Peterson, Jennifer;V. Sequist, Lecia;Gainor, Justin F.;Lennerz, Jochen K.;Digumarthy, Subba R.
• 通讯作者: Digumarthy, Subba R.