The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
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DOI：
10.1158/2159-8290.cd-19-1167
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发表时间：
2020-01-01
期刊：
影响因子：
28.2
通讯作者：
Christensen, James G.
中科院分区：
文献类型：
--
作者：
Hallin, Jill;Engstrom, Lars D.;Christensen, James G.
尽管进行了数十年的研究，但直接针对KRAS的努力一直在挑战。MRTX849被鉴定为一种有效的、选择性的和共价的KRAS（G1）（2C）抑制剂，其表现出有利的药物样特性，选择性地修饰GDP结合的KRAS（G1）（2C）中的突变型半胱氨酸12，并抑制KRAS依赖性信号传导。MRTX849在来自多种肿瘤类型的26个KRAS（G1）（2C）阳性细胞系和患者来源的异种移植物模型中的17个（65%）中表现出明显的肿瘤消退，并且在KRAS（G1）（2C）阳性肺和结肠腺癌患者中观察到客观缓解。在敏感和部分耐药非临床模型中进行的全面药效学和药物基因组学分析确定了限制抗肿瘤活性的机制，包括KRAS核苷酸循环和诱导反馈再激活和/或绕过KRAS依赖的途径。这些因素包括受体酪氨酸激酶（RTK）的激活，KRAS依赖的旁路，和细胞周期的遗传失调。MRTX849与靶向RTK、mTOR或细胞周期的药物组合在多种肿瘤模型（包括MRTX849难治性模型）中表现出增强的反应和显着的肿瘤消退。意义：MRTX849的发现提供了一个期待已久的机会选择性靶向患者的KRAS（G1）（2C）。MRTX849活性的深入表征、应答和耐药机制的阐明以及有效组合的鉴定为KRAS依赖性和这类药物的合理开发提供了新的见解。
Despite decades of research, efforts to directly target KRAS have been chal- lenging. MRTX849 was identified as a potent, selective, and covalent KRAS(G1)(2C) inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRAS(G1)(2C), and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRAS(G1)(2C)-positive cell line- and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRAS(G1)(2C)-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models.SIGNIFICANCE: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRAS(G1)(2C) in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.