Abstract LB-271: Insight towards therapeutic susceptibility of KRAS mutant cancers from MRTX1257, a novel KRAS G12C mutant selective small molecule inhibitor
Abstract LB-271: Insight towards therapeutic susceptibility of KRAS mutant cancers from MRTX1257, a novel KRAS G12C mutant selective small molecule inhibitor
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DOI：
10.1158/1538-7445.am2019-lb-271
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发表时间：
2019-07
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通讯作者：
J. Christensen;Jay B. Fell;M. Marx;J. Fischer;Jill Hallin;Andrew Calinisan;B. R. Baer;M. Burkhard;J. Blake;G. Vigers;Ruth Aranda;Lauren N. Hargis;David M Briere;Lars D. Engstrom;P. Olson
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作者：
J. Christensen;Jay B. Fell;M. Marx;J. Fischer;Jill Hallin;Andrew Calinisan;B. R. Baer;M. Burkhard;J. Blake;G. Vigers;Ruth Aranda;Lauren N. Hargis;David M Briere;Lars D. Engstrom;P. Olson
尽管经过数十年的研究，有效靶向突变 KRAS 的能力仍然难以捉摸。通过解决一系列共晶结构以及基于迭代结构的药物设计，取代的四氢吡啶并嘧啶被确定为突变型 KRAS G12C 的选择性共价抑制剂。 MRTX1257 作为一种研究工具化合物出现，证明能够不可逆地修饰 KRAS G12C，将其捕获在非活性 GDP 结合状态，并抑制 ERK1/2，IC50 值为 1 nM。因此，研究旨在深入了解治疗反应的广度和 MRTX1257 活性的潜在分子机制。在细胞活力测定中对 KRAS G12C 突变细胞系扩展组的评估表明，其具有广泛的抗肿瘤活性，具有可变的浓度反应模式（0.2-62 nM）。 MRTX1257 还在多种 KRAS G12C 突变肿瘤模型中证明了 KRAS G12C 的剂量依赖性不可逆修饰以及 KRAS 依赖性信号转导的抑制作用。然后以固定剂量水平对 MRTX1257 进行评估，结果显示近乎完全的 KRAS 靶标抑制具有广谱抗肿瘤活性，包括在大量 KRAS G12C 突变细胞来源和患者来源的异种移植物（n = 23）中评估的所有模型中约 80% 的深度肿瘤消退。 MRTX1257 在体外和体内的非 KRAS G12C 突变细胞系中均无活性。在 KRAS G12C 阳性模型中，不同肿瘤模型的抗肿瘤反应从持久的肿瘤完全消退到肿瘤停滞不等。一小部分模型表现出初始肿瘤快速消退，随后肿瘤停滞，表明可能存在对 MRTX1257 治疗的适应性耐受机制。基于这种反应模式，评估了信号转导和反馈信号通路。在与药物耐受动力学一致的时间模式中，根据 pERK 和 pS6 信号转导的反弹，在连续治疗后观察到 MAP 激酶途径重新激活。还观察到双特异性磷酸酶 (DUSP)、Sprouty 家族 (SPRY) 和 ETV 的下调以及细胞周期与 KRAS 监管限制的解耦，这与信号传导反弹动态和药物耐受性一致。 CRISPR 和小分子组合筛选将 mTOR、SHP2、EGFR 家族和细胞周期激酶确定为部分耐受的 KRAS G12C 突变模型中的可靶向漏洞。基于这些观察，在肿瘤模型中评估了许多旨在共同靶向信号反馈途径的组合策略，并深入了解了反弹途径的重要性。总之，这些数据表明了 KRAS G12C 突变阳性肿瘤的治疗敏感性和广泛依赖性，并提供了对单药和组合疗法反应的分子基础的见解。引文格式：James G. Christensen、Jay B. Fell、Matthew A. Marx、John Fischer、Jill Hallin、Andrew Calinisan、Brian Baer、Michael Burkhard、James Blake、Guy Vigers、Ruth Aranda、Lauren Hargis、David Briere、Lars Engstrom、Peter Olson。从 MRTX1257（一种新型 KRAS G12C 突变选择性小分子抑制剂）洞察 KRAS 突变癌症的治疗敏感性 [摘要]。见：2019 年美国癌症研究协会年会论文集； 2019年3月29日-4月3日；佐治亚州亚特兰大。费城（宾夕法尼亚州）：AACR；癌症研究 2019；79（13 增刊）：摘要 nr LB-271。
The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a series of co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C. MRTX1257 emerged as a research tool compound that demonstrates the ability to irreversibly modify KRAS G12C, trap it in its inactive GDP-bound state, and inhibit ERK1/2 with an IC50 value of 1 nM. Therefore, studies were designed to provide insight towards the breadth of therapeutic response and the underlying molecular mechanisms of MRTX1257 activity. The evaluation of an extended panel of KRAS G12C mutant cell lines in cell viability assays indicated broad anti-tumor activity with a variable concentration-response pattern (0.2-62 nM). MRTX1257 also demonstrated dose-dependent irreversible modification of KRAS G12C and inhibition of KRAS-dependent signal transduction in multiple KRAS G12C mutant tumor models. MRTX1257 was then evaluated at a fixed dose level which demonstrated near-complete KRAS target inhibition with broad spectrum anti-tumor activity including deep tumor regressions in approximately 80% of all models evaluated across a large panel of KRAS G12C-mutant cell-derived and patient-derived xenografts (n = 23). MRTX1257 was inactive in non-KRAS G12C-mutant cell lines in vitro and in vivo. The antitumor response across tumor models varied in KRAS G12C positive models from durable complete tumor regression to tumor stasis. A small subset of models demonstrated rapid initial tumor regression, followed by tumor stasis suggesting that there may be mechanisms of adaptive tolerance to MRTX1257 treatment. Based on this response pattern, signal transduction and feedback signaling pathways were evaluated. In a temporal pattern consistent with drug tolerance kinetics, MAP kinase pathway reactivation was observed following continuous treatment based on rebound of pERK and pS6 signaling. Also consistent with signaling rebound dynamics and drug tolerance, down-regulation of dual specificity phosphatases (DUSPs), Sprouty family (SPRY), and ETVs along with decoupling of cell cycle from KRAS regulatory constraints was observed. CRISPR and small molecule combination screens identified mTOR, SHP2, EGFR family, and cell cycle kinases as targetable vulnerabilities in partially tolerant KRAS G12C mutant models. Based on these observations, a number of combination strategies designed to co-target signaling feedback pathways were evaluated in tumor models and provided insight into the importance of rebound pathways. Together, these data indicate the therapeutic susceptibility and broad dependence of KRAS G12C mutation-positive tumors and provide insight toward the molecular basis of response to single agent and combinatorial therapies. Citation Format: James G. Christensen, Jay B. Fell, Matthew A. Marx, John Fischer, Jill Hallin, Andrew Calinisan, Brian Baer, Michael Burkhard, James Blake, Guy Vigers, Ruth Aranda, Lauren Hargis, David Briere, Lars Engstrom, Peter Olson. Insight towards therapeutic susceptibility of KRAS mutant cancers from MRTX1257, a novel KRAS G12C mutant selective small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-271.