KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition
KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition
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DOI：
10.1158/1078-0432.ccr-18-0368
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发表时间：
2019-01-15
影响因子：
11.5
通讯作者：
Benes, Cyril H.
中科院分区：
文献类型：
--
作者：
Misale, Sandra;Fatherree, Jackson P.;Benes, Cyril H.
目的：KRAS突变型肺癌已被包括靶向MAPK通路的治疗所取代。KRAS p.G12C等位基因的共价抑制剂允许直接和特异性抑制癌细胞中的突变型KRAS。然而，对于其他靶向治疗，这些抑制剂的治疗潜力可能会受到内在耐药机制的损害。实验设计：为了确定最大限度地利用直接KRAS抑制的策略，我们定义了一组携带KRAS G12 C激活突变的NSCLC模型在体外和体内的反应。我们使用了第二代KRAS G12 C抑制剂ARS 1620，其生物利用度比第一代有所提高。我们分析了KRAS下游效应物信号传导，以确定差异反应的潜在机制。为了确定候选组合策略，我们对112种药物与ARS 1620的组合进行了高通量药物筛选。我们在体外和体内（包括患者来源的异种移植物模型）验证了最高命中率。结果：对直接KRAS G12 C抑制的反应在模型间是异质的。适应性抗性机制涉及MAPK途径的重新激活和未能诱导PI 3 K-AKT途径失活被确定为可能的抗性事件。我们鉴定了几种模型特异性有效组合以及PI 3 K-AKT-mTOR通路抑制剂的广泛致敏作用。G12 Ci + PI 3 Ki组合在体外和体内对单药ARS 1620耐药模型（包括患者来源的异种移植物模型）有效。结论：我们的研究结果表明，信号适应在某些情况下可以限制ARS 1620的功效，但与PI 3 K抑制剂联合使用可以克服这种耐药性。
Purpose: KRAS-mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy.Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C-activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient-derived xenograft models.Results: Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K-AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad-sensitizing effect of PI3K-AKT-mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single-agent ARS1620 including patient-derived xenografts models.Conclusions: Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.