Overcoming resistance to targeted therapy in cancer

 描述（由申请人提供）：克服癌症靶向治疗的耐药性项目概述耐药性的挑战代表了一个普遍的障碍，混淆了治愈或长期控制转移性癌症的最终目标。近年来，我们小组对靶向治疗耐药性的深入研究揭示了三个过度挑战。首先，耐药是多因素的：许多个体耐药机制阻碍了各种靶向抗癌治疗方案的疗效，并且没有证据表明它们的发现已经饱和。其次，耐药是异质性的：在特定患者中经常出现多种不同的耐药机制-甚至在单个肿瘤病变中1。第三，在临床竞技场中，耐药性的采样严重不足：临床上很少获得配对的治疗前和耐药后活检，并且这些组织很少进行系统表征2。这项研究的指导假设是，任何给定的癌症治疗方式的耐药机制谱可能会合并到一组小得多的关键下游效应“节点”上。辨别这种“聚结点”内的运作机制，应产生新的见解致癌的依赖性和照明设计新的治疗组合的指导原则。近年来，我们通过系统地表征BRAF突变型黑色素瘤和其他癌基因驱动的癌症中对MAP激酶途径抑制的抗性机制来评估这种“聚结假说”。事实上，许多个别MAP激酶抗性机制可能在转录（或染色质）调节水平上合并。这种融合重新接合核心MAPK转录程序或由旁路信号传导产生的替代（ERK非依赖性）转录程序或与“途径无关”细胞状态密切相关。因此，这项工作的一个目标是确定收敛的下游输出详细的MAP激酶抑制剂的耐药机制，以及控制它们的因素。同时，我们将描述其他癌症中靶向治疗的耐药机制的合并。最后，我们将描述在难治性肿瘤中的耐药和“药物无关”细胞状态。详细 耐药类别的表征和其中隐含的机械聚结可以揭示对癌症依赖性的性质及其在肿瘤进展和治疗期间的演变的基本新见解。从这项研究中获得的见解可能有助于设计攻击多种肿瘤依赖性和耐药节点的高阶治疗组合。这种研究耐药性的机制聚结的框架适用于许多癌症类型。因此，这些努力可以提供指导原则，使其在许多肿瘤类型和治疗方式中具有普遍性。

 DESCRIPTION (provided by applicant): Overcoming resistance to targeted therapy in cancer Project Summary The challenge of drug resistance represents a pervasive barrier that confounds the ultimate goal of cure or long-term control of metastatic cancer. Intensive studies of resistance to targeted therapies by our group in recent years have revealed three over-arching challenges. First, resistance is multifactorial: many individual resistance mechanisms thwart the efficacy of various targeted anticancer therapeutic regimens, and there is no evidence that their discovery has saturated. Second, resistance is heterogeneous: multiple different resistance mechanisms often arise in a given patient-even within a single tumor lesion1. Third, resistance is vastly under-sampled in the clinical arena: few paired pre-treatment and post-resistance biopsies are obtained clinically, and such tissues are only seldom subjected to systematic characterization2. The guiding hypothesis of this research is that the spectrum of resistance mechanisms for any given cancer therapeutic modality might coalesce onto a much smaller set of critical downstream effector "nodes". Discerning the mechanisms operant within such "points of coalescence" should yield new insights into oncogenic dependencies and illuminate guiding principles for the design of novel therapeutic combinations. In recent years, we have evaluated this "coalescence hypothesis" by systematically characterizing mechanisms of resistance to MAP kinase pathway inhibition in BRAF-mutant melanoma and other oncogene- driven cancers. Indeed, many individual MAP kinase resistance mechanisms may coalesce at the level of transcriptional (or chromatin) regulation. This convergence re-engages core MAPK transcriptional program(s) or alternative (ERK-independent) transcriptional programs arising from bypass signaling or germane to "pathway-indifferent" cell states. Accordingly, one objective of this work is to define the convergent downstream outputs elaborated by MAP kinase inhibitor resistance mechanisms, and the factors that govern them. In parallel, we will characterize the coalescence of resistance mechanisms to targeted therapeutics in other cancers. Finally, we will describe drug-resistant and "drug-indifferent" cell states in treatment-refractory tumors. Detailed characterization of resistance categories and the mechanistic coalescence implied therein may reveal fundamental new insights into the nature of cancer dependencies and their evolution during tumor progression and treatment. Insights gleaned from this research may aid the design of higher-order therapeutic combinations that attack multiple tumor dependencies and resistance nodes. This framework for studying the mechanistic coalescence that underpins drug resistance is applicable to many cancer types. Therefore, these efforts could offer guiding principles that become generalizable across many tumor types and therapeutic modalities.