Overcoming resistance to targeted therapy in cancer

 描述(申请人提供)：在癌症项目摘要中克服靶向治疗的阻力抗药性的挑战是一个普遍存在的障碍，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的耐药性进行了深入的研究，揭示了三个突出的挑战。首先，耐药性是多因素的：许多个体耐药性机制阻碍了各种靶向抗癌治疗方案的疗效，而且没有证据表明它们的发现已经饱和。其次，耐药性是异质性的：在给定的患者中经常出现多种不同的耐药性机制--甚至在单个肿瘤病变中也是如此。第三，在临床领域，耐药性的抽样严重不足：临床上很少获得成对的治疗前和耐药后活检组织，而且这些组织很少受到系统特征的影响。这项研究的指导性假设是，任何给定的癌症治疗方式的耐药机制的光谱可能会结合到一组更小的关键下游效应器“节点”上。弄清这种“结合点”内的作用机制应该会对致癌相关性产生新的见解，并阐明设计新的治疗组合的指导原则。近年来，我们通过系统地描述BRAF突变黑色素瘤和其他癌基因驱动的癌症对MAPK通路抑制的抵抗机制，评估了这一“合并假说”。事实上，许多单独的MAP激酶抵抗机制可能在转录(或染色质)调节水平上结合在一起。这种融合重新启动核心MAPK转录程序(S)或替代(ERK不依赖)转录程序，这些转录程序由旁路信号或与之相关的信号转导到“通路无关”的细胞状态。因此，这项工作的一个目标是定义MAP激酶抑制剂耐药机制所阐述的收敛的下游输出，以及控制它们的因素。同时，我们将描述在其他癌症中对靶向治疗药物的耐药机制的联合。最后，我们将描述治疗难治性肿瘤中耐药和“药物无关”的细胞状态。详细 耐药类别的特征和其中隐含的机制结合可能揭示癌症依赖的性质及其在肿瘤进展和治疗过程中的演变。从这项研究中收集到的见解可能有助于设计更高层次的治疗组合，攻击多个肿瘤依赖性和耐药节点。这一研究耐药机制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，使之适用于许多肿瘤类型和治疗方式。

 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.