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.

项目概要 携带致癌间变性淋巴瘤激酶 (ALK) 基因的非小细胞肺癌 (NSCLC) 重排（即“ALK+”）包含肺癌的一个独特的分子亚型，对 ALK 具有显着敏感性 酪氨酸激酶抑制剂（TKI）。虽然 ALK TKI 最初非常有效，但获得性耐药性仍然存在 这是限制临床获益并导致大多数患者疾病复发的根本挑战。我们和其他人 具有特征性的耐药机制，特别是由 继发性获得性 ALK 激酶结构域突变可以通过更有效的下一代（第 2- 或第三代）抑制剂。近年来，诊断患有以下疾病的患者的标准治疗模式 晚期 ALK+ 肺癌已从使用第一代 ALK TKI 克唑替尼序贯治疗转变 其次是下一代 TKI，再到预先使用下一代 ALK TKI 进行初始治疗。我们的初步数据 表明脱靶（即不依赖 ALK）耐药机制在下一代药物之后普遍存在 ALK TKI。然而，一系列脱靶抵抗机制和克服这些机制的策略仍然存在 人们对此知之甚少，这给这些患者的治疗选择的开发带来了障碍。这 拟议研究的总体目标是确定和开发互补的、基于机制的 以及克服对下一代 ALK TKI 脱靶耐药的机制不可知方法。我们将 对扩大的患者肿瘤样本队列进行全面的基因组和非基因组评估 确定一线使用下一代 ALK 后脱靶耐药机制的临床谱 TKI，我们将开发新方法来识别最有可能患有旁路介导耐药的患者 受益于合理设计的联合疗法。使用源自以下来源的 ALK TKI 耐药肿瘤细胞系 对患者进行活检，我们将筛选独立于典型旁路而驱动耐药性的表观遗传机制 信号通路，最初的研究重点是确定转录辅激活因子 p300/CBP 的作用 作为脱靶 ALK TKI 耐药性和治疗靶点的新型驱动因素。这些努力将使针对特定患者的、 机制知情的治疗策略。与此同时，我们将开发一种与机制无关的方法 利用 ALK 作为肿瘤特异性“新抗原”，其表达在耐药肿瘤中得以维持。使用 T 基于细胞的功能筛选，我们将鉴定能够 识别耐药 ALK+ NSCLC。这将为工程 ALK TCR 过继细胞奠定基础 疗法作为 TKI 正交、基于免疫的方法来克服耐药性。总的来说，拟议的 研究将提供对下一代 ALK TKI 耐药性的全面了解并铺平道路 开发新的治疗策略，可以有效克服大多数脱靶耐药性 诊所，最终改善并延长晚期 ALK+ 肺癌患者的生命。

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.