Development of Novel Combination Strategies to Overcome Resistance to KRASG12C Inhibition in Colorectal Cancers

项目摘要/摘要 被诊断为晚期KRAS突变的结直肠癌患者的总体生存时间大致为 一年。尽管出现了越来越多的分子靶向药物，但 患有这些癌症的患者仍然很差，5年存活率为10%。最近，进展是 在针对KRASG12C突变的治疗药物的临床进展中取得了进展，这些突变是 存在于大约5%的结直肠肿瘤中。然而，使用KRASG12C进行的单一疗法试验 目标代理人虽然令人鼓舞，但令人失望的是缺乏持久的反应，这决定了需要 用于组合方法。已知EGFR重新激活MAPK信号通路以响应下游 干预，这一事件因PI3K/mTOR通路在调节中的作用而变得更加复杂 抵抗。这一提议的中心假设是，一种双重的小分子抑制剂可以有效地 选择性靶向EGFR和PI3激酶代表了一种可行的治疗策略，与 KRASG12C抑制剂临床候选药物AMG-510。为了验证这一假设，我们设计了小分子 表现出对EGFR和PI3K家族成员的有效和选择性的双重抑制。我们建议进行一项 我们的双EGFR/PI3K先导分子MTX-531联合AMG-510在异种移植模型中的小鼠实验 从确诊为KRASG12C突变的结直肠癌患者中建立。分子图谱将会是 用来阐明与固有敏感性以及适应性信号相关的标记 导致进步的变化。应答者模型将在验证性测试中进行重新评估 与西妥昔单抗和AMG-510联合用药的头部比较。这项提议的总体目标是 展示临床前概念验证，以追求这一发展道路，以优化治疗 MTX-531作为治疗KRASG12C突变结直肠癌的精确药物途径的潜力 癌症。

PROJECT SUMMARY/ABSTRACT Patients diagnosed with advanced stage KRAS mutant colorectal cancer have an overall survival of roughly one year. Despite the emergence of an increased number of molecular targeted agents, the prognosis for patients with these cancers remains poor with 5-year survival rates of <10%. Recently, progress has been made in the clinical advancement of therapeutics directed specifically against KRASG12C mutations, which are present in roughly five percent of colorectal tumors. However, monotherapy trials conducted with KRASG12C targeted agents, while encouraging, have met with disappointing lack of durable responses, dictating the need for combination approaches. EGFR is known to reactivate MAPK kinase signaling in response to downstream intervention, an event that is further complicated by the role of the PI3K/mTOR pathway in mediating resistance. The central hypothesis of this proposal is that a dual small molecule inhibitor that potently and selectively targets both EGFR and PI3 kinase represents a viable treatment strategy in combination with the KRASG12C inhibitor clinical candidate AMG-510. To test this hypothesis, we have designed small molecules that exhibit potent and selective dual inhibition of EGFR and PI3K family members. We propose to carry out a mouse trial of our dual EGFR/PI3K lead molecule MTX-531 in combination with AMG-510 in xenograft models established from patients diagnosed with KRASG12C mutant colorectal cancer. Molecular profiling will be carried out to elucidate markers that correlate with inherent sensitivity as well as the adaptive signaling changes that lead to progression. Responder models will be re-evaluated in confirmatory testing in head-to- head comparison with the combination of cetuximab and AMG-510. The overall objective of this proposal is to demonstrate preclinical proof of concept for pursuit of this development path to optimize the therapeutic potential of MTX-531 as a precision medicine approach for the treatment of KRASG12C mutant colorectal cancer.