Targeting Acquired Resistance in KRAS Driven Cancers

治疗抗性的发展是有效癌症治疗的主要障碍。KRASG 12 C抑制剂 （KRASi）最近已被FDA批准，代表了一种有前途的新型癌症靶向治疗方法 KRAS突变是在人类癌症中观察到的最常见的基因突变之一。然而， 在标准治疗的情况下，大多数最初对KRASi有反应的肿瘤迅速发展为耐药 疾病不幸的是，KRASi抗性的潜在机制知之甚少。解决这个 具有挑战性的问题，该应用程序将利用PI在KRAS领域的跟踪记录和专业知识 信号和生物学，并提出一个全面的研究计划，重点是了解 对KRAS靶向治疗的获得性耐药机制。此应用程序将识别新的可操作 治疗目标和方法，以克服耐药性，从而大大改善临床结果 KRAS突变癌症患者。为了实现这一点，姚实验室在体外和体内开发了 模型系统，将用于调查有关机制的假设，推动发展 KRASi的抵抗体外模型系统由KRAS依赖性和非依赖性细胞培养物组成 来源于胰腺癌的基因工程小鼠模型以及 胰腺和结肠来源。体内模型系统由患者来源的结肠癌模型组成， 开发了对KRASi的耐药性，以及由KRASi驱动的胰腺癌基因工程小鼠模型。 KRASG12C。要解决的主要知识差距是：i）激活哪些分子事件， ii）这些分子事件如何起作用以驱动 肿瘤存活和维持对KRASi的响应;和iii）是否药物靶向耐药 该机制可以与KRASi组合实现持久的治疗反应。这些研究将揭示一个 肿瘤细胞对KRAS靶向治疗产生抗性的先前未知的机制， 为KRASi耐药患者定义了一种创新的治疗选择。拟议的工作包括一项重要的 朝着我们为KRAS突变癌症患者开发有效治疗的长期目标迈出了一步， 国家癌症研究所（NCI）RAS倡议（“杀死RAS”）的使命。

Development of treatment resistance is a major impediment to effective cancer therapy. KRASG12C inhibitors (KRASi) have been recently approved by FDA and represents a promising new targeted therapy for cancer types with KRAS mutation, one of the most frequent genetic mutations observed in human cancers. However, as is the case with standard therapy, majority of tumors that initially respond to KRASi quickly develop resistant disease. Unfortunately, the underlying mechanisms of KRASi resistance are poorly understood. To tackle this challenging problem, this application will capitalize on the PI's track record and expertise in the area of KRAS signaling and biology and propose a comprehensive research program focusing on understanding the mechanisms of acquired resistance to KRAS targeted therapy. This application will identify new actionable therapeutic targets and approaches to overcome resistance, thus greatly improving the clinical outcome of patients with KRAS mutated cancers. To achieve this, the Yao laboratory has developed in vitro and in vivo model systems that will be employed to investigate hypotheses regarding mechanisms driving the development of KRASi resistance. The in vitro model system consists of KRAS dependent and independent cell cultures derived from genetically engineered mouse models of pancreatic cancer as well as human cancer cell lines of pancreatic and colon origin. The in vivo model system consists of patient-derived colon cancer models that developed resistance to KRASi, as well as genetically engineered mouse models of pancreatic cancer driven by KRASG12C. The major knowledge gaps to be addressed are that: i) what molecular events are activated to enable bypass of KRAS dependency in tumors treated with KRASi; ii) how these molecular events function to drive tumor survival and maintenance in response to KRASi; and iii) whether pharmaceutically targeting the resistant mechanism can achieve durable therapeutic responses in combination with KRASi. These studies will unveil a previously unknown mechanism by which tumor cells become resistant to KRAS targeted therapy and may define an innovative therapeutic option for KRASi-resistant patients. The proposed work comprises an essential step toward our long-term goal of developing effective therapy for patients with KRAS mutated cancer, in align with the mission of the National Cancer Institute (NCI) RAS initiative (“Kill RAS”).