Targeting Acquired Resistance in KRAS Driven Cancers

治疗耐药性的产生是癌症有效治疗的主要障碍。KRASG12C抑制剂 (Krasi)最近获得了FDA的批准，代表着一种有前途的针对癌症类型的新靶向疗法 KRAS突变，这是在人类癌症中观察到的最常见的基因突变之一。然而，正如所说的那样 在标准治疗的情况下，大多数最初对Krasi有反应的肿瘤很快就会产生耐药性 疾病。不幸的是，Krasi抗性的潜在机制尚不清楚。来解决这个问题 具有挑战性的问题，这一应用程序将利用PI在KRAS领域的记录和专业知识 信号和生物学，并提出一个全面的研究计划，重点是了解 KRAS靶向治疗获得性耐药的机制。此应用程序将识别新的可操作的 克服耐药性的治疗靶点和方法，从而极大地改善临床结果 患有KRAS的患者突变了癌症。为了实现这一点，姚实验室在体外和体内都进行了开发 将用于研究有关驱动开发的机制的假设的模型系统 克拉西抵抗组织。体外模型系统由KRAS依赖和独立的细胞培养组成 来源于转基因小鼠胰腺癌模型以及人胰腺癌细胞系 起源于胰腺和结肠。体内模型系统由患者来源的结肠癌模型组成， 对Krasi产生了抵抗力，以及由Krasi驱动的胰腺癌基因工程小鼠模型 KRASG12C。需要解决的主要知识差距是：i)哪些分子事件被激活以使 Krasi治疗的肿瘤中对KRAS依赖的旁路；II)这些分子事件如何发挥驱动作用 Krasi反应的肿瘤存活和维持；以及iii)是否药物靶向耐药 该机制与Krasi联合使用可实现持久的治疗效果。这些研究将揭示一种 以前未知的肿瘤细胞对KRAS靶向治疗产生抗药性的机制可能 为耐Krasi的患者确定一种创新的治疗方案。拟议的工作包括一个基本的 朝着我们的长期目标迈进一步，即为ALIGN的KRAS突变癌症患者开发有效的治疗方法 与国家癌症研究所(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”).