Mechanisms driving lung cancer evolution during targeted kinase inhibitor treatment

项目摘要/摘要： 抑制致癌激酶的靶向治疗，如EGFR、ALK、ROS1(TKI)已有显著改善 肺癌患者的生存，其肿瘤存在激活这些基因的基因组变化。 不幸的是，这些疗法不能治愈，患者最终会产生抗药性，导致 疾病的发展。我们团队和其他人最近的工作已经证明， 获得性耐药可从最初在药物治疗中存活的残留耐药细胞进化而来 然后在治疗过程中随后获得基因组改变。这表明，治疗策略 可以改变残留肿瘤细胞的生存和进化，可能会先发制人，出现耐药克隆。在……里面 使用EGFR突变和ALK融合肺癌的临床前模型的初步研究，我们观察到 在最初的TKI治疗中存活的癌细胞显示APOBEC3A表达和活性增加 胞苷脱氨酶。此外，EGFR和ALK肺癌患者的临床肿瘤标本分析 发现在TKI序贯治疗期间APOBEC突变积累。我们假设APOBEC3A- TKI诱导的DNA和RNA编辑促进耐药克隆的出现 肺癌在治疗过程中，并促进获得性耐药的演变。在这个项目中，我们将 开发新的生化和计算工具来研究EGFR突变体和ALK中APOBEC3A的突变 融合非小细胞肺癌实验模型和临床肿瘤标本。这些研究将确定 TKI治疗和APOBEC诱变之间的因果联系。接下来，我们将调查是否 先天免疫信号通路对基因组不稳定和/或RNA表达的响应 重复元件是TKI诱导APOBEC3A突变的必要条件和充分条件。最后，我们将确定 APOBEC3A的诱导是否促进耐药克隆的存活和随后的发展 获得性抗药性。这些研究将对TKI耐药性如何演变产生基本的生物学见解 在癌基因成瘾癌症中的作用，并识别可针对延迟或预防耐药性的新的脆弱性 从显影开始。

Project Summary/Abstract: Targeted therapies that inhibit oncogenic kinases such as EGFR, ALK, ROS1 (TKIs) have significantly improved the survival of lung cancer patients whose tumors harbor activating genomic alterations in these genes. Unfortunately, these therapies are not curative and patients eventually develop drug resistance leading to disease progression. Recent work by our group and others has demonstrated that genomic mechanisms of acquired drug resistance can evolve from residual drug-tolerant cells that that initial survive drug treatment and then subsequently acquire the genomic alteration during therapy. This suggests that treatment strategies that can alter the survival and evolution of residual tumor cells may pre-empt the emergence of resistant clones. In preliminary studies using preclinical models of EGFR mutant and ALK fusion lung cancer, we have observed that cancer cells surviving initial TKI treatment exhibit increased expression and activity of the APOBEC3A cytidine deaminase. Additionally, analysis of clinical tumor samples from EGFR and ALK lung cancer patients revealed accumulation of APOBEC mutations during sequential TKI therapy. We hypothesize that APOBEC3A- mediated DNA and RNA editing induced by TKI treatment facilitates the emergence of drug tolerant clones in lung tumors during treatment and facilitates the evolution of acquired drug resistance. In this project, we will develop novel biochemical and computational tools to study APOBEC3A mutagenesis in EGFR mutant and ALK fusion non-small cell lung cancer experimental models and clinical tumor specimens. These studies will establish a causal link between TKI treatment and induction of APOBEC mutagenesis. Next, we will investigate whether activation of innate immune signaling pathways in response to genomic instability and/or expression of RNA repeat elements is necessary and sufficient for TKI-induced APOBEC3A mutagenesis. Finally, we will determine whether induction of APOBEC3A promotes the survival of drug tolerant clones and subsequent development of acquired drug resistance. These studies will yield fundamental biological insights into how TKI resistance evolves in oncogene-addicted cancers and identify new vulnerabilities that can be targeted to delay or prevent resistance from developing.