Non-genomic resistance mechanisms in EGFR-mutant lung cancer

EGFR突变肺癌的非基因组耐药机制

• 批准号: 10623286
• 负责人: Aaron N Hata
• 金额: $ 39.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623286
• 关键词: Automobile Driving; BRAF gene; Biological Assay; Biopsy; Blood; Cancer Patient; Cells; Clinical; Clinical Research; Complement; DNA Sequence Alteration; Development; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Fibroblasts; Future; Gene Expression Profile; Generations; Genomics; Histologic; Immune; Infrastructure; Investigation; Laboratories; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular Analysis; Mutation; Non-Small-Cell Lung Carcinoma; Patient Care; Patients; Pharmaceutical Preparations; Plasma; Population Heterogeneity; Quality of life; RNA; Resistance; Role; Stromal Neoplasm; Tissues; Tumor Cell Line; Tumor Tissue; acquired drug resistance; clinically relevant; cohort; drug resistance development; effective therapy; immune activation; improved; innovation; liquid biopsy; molecular targeted therapies; mutant; neoplastic cell; new therapeutic target; non-genomic; novel; novel therapeutics; pre-clinical; relapse patients; resistance mechanism; resistance mutation; response; standard of care; targeted treatment; therapy development; tumor; tumor heterogeneity; tumor microenvironment

Project Summary Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is the current standard of care for first-line therapy for EGFR mutant lung cancer patients. While osimertinib is effective in inducing tumor regressions, improving quality of life and prolonging survival in most patients, it is not curative. Early studies of acquired resistance suggest that even after standard histologic and genomic assessments for resistance mechanisms, a substantial portion of osimertinib resistance remains uncharacterized. This incomplete understanding of osimertinib resistance poses a significant barrier to developing new and effective therapies for clinical use. We hypothesize that, in contrast to earlier generation EGFR inhibitors, non-genomic mechanisms are driving the majority of acquired resistance to first-line osimertinib. To date, assessments of EGFR TKI acquired resistance mechanisms have focused on genomic resistance mutations, amplifications, and fusions, in part because these can be readily detected in tumor tissue or in blood-based ctDNA liquid biopsies. In this project we seek to discover the spectrum of non-genomic osimertinib resistance. Our main objective is to identify both tumor intrinsic mechanisms of osimertinib resistance as well as tumor extrinsic microenvironmental resistance mechanisms. In Aim 1, we will use RARE-Seq, a novel blood-based assay to quantify tumor gene expressions patterns of resistance in EGFR mutant NSCLC patients relapsing on osimertinib. In Aim 2, we will investigate tumor cell extrinsic mechanisms of osimertinib resistance by leveraging our robust translational infrastructure to develop cancer-associated fibroblast models from osimertinib resistance biopsies. We will use these models to dissect functional interactions between CAFs, tumor cells and immune cells, and we will integrate these results with spatial molecular analysis of clinical biopsies. Collectively, the studies described in this proposal will generate a comprehensive picture of osimertinib resistance and set the stage for future development of therapies that overcome resistance to osimertinib.

项目概要 奥希替尼是第三代 EGFR 酪氨酸激酶抑制剂 (TKI)，是目前一线治疗的标准治疗 EGFR突变肺癌患者的治疗。虽然奥西替尼可有效诱导肿瘤消退， 虽然它可以改善大多数患者的生活质量并延长生存期，但它并不能治愈。获得性的早期研究 耐药性表明，即使在对耐药机制进行标准组织学和基因组评估后， 奥西替尼耐药性的很大一部分仍然未知。这种不完全的理解 奥希替尼耐药性对开发临床使用的新的有效疗法构成了重大障碍。我们 假设与早期一代 EGFR 抑制剂相比，非基因组机制正在推动 大多数对一线奥希替尼产生耐药性。迄今为止，EGFR TKI 获得性耐药的评估 机制主要集中在基因组抗性突变、扩增和融合上，部分原因是这些 可以在肿瘤组织或基于血液的 ctDNA 液体活检中轻松检测到。在这个项目中，我们寻求 发现非基因组奥希替尼耐药谱。我们的主要目标是识别肿瘤内在 奥希替尼耐药机制以及肿瘤外在微环境耐药机制。在 目标 1，我们将使用 RARE-Seq，一种新型的基于血液的检测方法来量化肿瘤基因表达模式 EGFR 突变 NSCLC 患者对奥希替尼复发的耐药性。在目标 2 中，我们将研究肿瘤细胞 通过利用我们强大的转化基础设施来开发奥西替尼耐药的外在机制 来自奥西替尼耐药活检的癌症相关成纤维细胞模型。我们将使用这些模型来剖析 CAF、肿瘤细胞和免疫细胞之间的功能相互作用，我们将把这些结果与 临床活检的空间分子分析。总的来说，本提案中描述的研究将产生 全面了解奥西替尼耐药性，并为未来开发治疗方法奠定基础 克服对奥西替尼的耐药性。

项目成果

Patient-derived models of acquired resistance can identify effective drug combinations for cancer.

• DOI: 10.1126/science.1254721
• 发表时间: 2014-12-19
• 期刊: Science (New York, N.Y.)
• 作者: Crystal AS;Shaw AT;Sequist LV;Friboulet L;Niederst MJ;Lockerman EL;Frias RL;Gainor JF;Amzallag A;Greninger P;Lee D;Kalsy A;Gomez-Caraballo M;Elamine L;Howe E;Hur W;Lifshits E;Robinson HE;Katayama R;Faber AC;Awad MM;Ramaswamy S;Mino-Kenudson M;Iafrate AJ;Benes CH;Engelman JA
• 通讯作者: Engelman JA

Acquired resistance to crizotinib from a mutation in CD74-ROS1.

• DOI: 10.1056/nejmoa1215530
• 发表时间: 2013-06-20
• 期刊: The New England journal of medicine
• 作者: Awad MM;Katayama R;McTigue M;Liu W;Deng YL;Brooun A;Friboulet L;Huang D;Falk MD;Timofeevski S;Wilner KD;Lockerman EL;Khan TM;Mahmood S;Gainor JF;Digumarthy SR;Stone JR;Mino-Kenudson M;Christensen JG;Iafrate AJ;Engelman JA;Shaw AT
• 通讯作者: Shaw AT

Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer.

• DOI: 10.3390/cancers13112666
• 发表时间: 2021-05-28
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Cabanos HF;Hata AN
• 通讯作者: Hata AN

Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer.

• DOI: 10.1200/po.17.00263
• 发表时间: 2018
• 期刊: JCO precision oncology
• 影响因子: 4.6
• 作者: Piotrowska Z;Hazar-Rethinam M;Rizzo C;Nadres B;Van Seventer EE;Shahzade HA;Lennes IT;Iafrate AJ;Dias-Santagata D;Leshchiner I;Jessop NA;Hu H;Digumarthy SR;Nagy RJ;Lanman RB;Moody S;Niederst MJ;Engelman JA;Hata AN;Corcoran RB;Sequist LV
• 通讯作者: Sequist LV

Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.

• DOI: 10.1158/2159-8290.cd-15-0399
• 发表时间: 2015-07
• 期刊: Cancer discovery
• 影响因子: 28.2
• 作者: Piotrowska Z;Niederst MJ;Karlovich CA;Wakelee HA;Neal JW;Mino-Kenudson M;Fulton L;Hata AN;Lockerman EL;Kalsy A;Digumarthy S;Muzikansky A;Raponi M;Garcia AR;Mulvey HE;Parks MK;DiCecca RH;Dias-Santagata D;Iafrate AJ;Shaw AT;Allen AR;Engelman JA;Sequist LV
• 通讯作者: Sequist LV