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.

项目摘要 非小细胞肺癌（NSCLC）具有致癌性促淋巴瘤激酶（ALK）基因 重排（即“ ALK+”）包含一个明显的肺癌分子子集，对碱的敏感性显着 酪氨酸激酶抑制剂（TKIS）。尽管ALK TKI最初是高效的，但获得的耐药性仍然存在 一个限制临床益处并导致大多数患者疾病的基本挑战。我们和其他人 具有抗药性机制，特别是所谓的“目标”抗性。 次级获得的ALK激酶结构域突变，可以通过更大的下一代来克服（第二代 或第三代抑制剂。近年来，诊断为患者的标准治疗范例 先进的ALK+肺癌已从使用第一代ALK TKI Crizotinib从顺序治疗转移 其次是下一代TKI，使用下一代ALK TKI前期进行初始治疗。我们的初步数据 表明下一代之后的脱靶（即无碱独立）的电阻机制很普遍 Alk tkis。然而，脱靶抵抗机制和克服策略的范围仍然存在 了解不足，为这些患者开发治疗方案的障碍带来了障碍。 拟议的研究的总体目标是识别和发展完整性，机制信息 和机制 - 敏锐的方法，用于克服对下一代ALK TKIS的脱靶耐药性。我们将 使用扩展的患者肿瘤标本的综合基因组和非基因组评估 确定一线使用下一代ALK后脱靶抗性机制的临床光谱 TKIS，我们将开发新的方法来识别旁路介导的抗药性的患者 受益于合理设计的组合疗法。使用衍生自ALK TKI TKI耐药性肿瘤细胞系 患者活检，我们将筛选出具有独立于规范旁路的耐药性的表观遗传机制 信号通路，最初的研究重点是定义转录共激活器P300/CBP的作用 作为脱靶ALK TKI耐药性和治疗靶标的新颖驱动力。这些努力将使特定于患者， 机制信息理论策略。同时，我们将开发一种机制 - 敏捷的方法 利用ALK作为一种肿瘤特异性的“新抗原”，其表达保持在抗性肿瘤中。使用t 基于细胞的功能屏幕，我们将确定能够具有的ALK反应性T细胞受体（TCR） 识别抗性ALK+ NSCLC。这将为工程ALK TCR自适应细胞提供基础 治疗是一种克服抗性的TKI正交，基于免疫的方法。共同提议 研究将为对下一代ALK TKIS的抵抗力提供​​全面的理解，并为方式铺平道路 为了制定新的治疗策略，这些策略可以有效地克服大多数脱离目标的阻力 该诊所最终改善和延长了晚期ALK+肺癌患者的寿命。

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.

• 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

Circulating Tumor DNA Identifies EGFR Coamplification as a Mechanism of Resistance to Crizotinib in a Patient with Advanced MET-Amplified Lung Adenocarcinoma.

循环肿瘤 DNA 确定 EGFR 共扩增是晚期 MET 扩增肺腺癌患者对克唑替尼耐药的机制。

• DOI: 10.1016/j.jtho.2017.04.023
• 发表时间: 2017
• 期刊: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
• 作者: Dagogo-Jack,Ibiayi;Fabrizio,David;Lennerz,Jochen;Schrock,AlexaB;Young,Lauren;Mino-Kenudson,Mari;Digumarthy,SubbaR;Heist,RebeccaS;Ali,SirajM;Miller,VincentA;Shaw,AliceT
• 通讯作者: Shaw,AliceT

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.