Approximately 15% of all cancer patients harbor mutated KRAS. Direct inhibitors of KRAS have now been generated and are beginning to make progress through clinical trials. These include a suite of inhibitors targeting the KRASG12C mutation commonly found in lung cancer. We investigated emergent resistance to representative examples of different classes of Ras targeted therapies. They all exhibited rapid reactivation of Ras signaling within days of exposure and adaptive responses continued to change over long-term treatment schedules. Whilst the gene signatures were distinct for each inhibitor, they commonly involved up-regulation of upstream nodes promoting mutant and wild-type Ras activation. Experiments to reverse resistance unfortunately revealed frequent desensitization to members of a panel of anti-cancer therapeutics, suggesting that salvage approaches are unlikely to be feasible. Instead, we identified triple inhibitor combinations that resulted in more durable responses to KRAS inhibitors and that may benefit from further pre-clinical evaluation.

中文翻译：

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减轻对 KRAS 靶向治疗耐药性的组合方法

大约 15% 的癌症患者携带 KRAS 突变。现在已经产生了 KRAS 的直接抑制剂，并开始通过临床试验取得进展。其中包括一套针对肺癌中常见的 KRASG12C 突变的抑制剂。我们调查了对不同类别的 Ras 靶向治疗的代表性例子的紧急耐药性。他们都在暴露后的几天内表现出Ras信号的快速重新激活，并且适应性反应在长期治疗计划中继续发生变化。虽然每种抑制剂的基因特征不同，但它们通常涉及上游节点的上调，促进突变型和野生型 Ras 激活。不幸的是，逆转耐药性的实验揭示了对一组抗癌疗法成员的频繁脱敏，表明打捞方法不太可能是可行的。相反，我们确定了对 KRAS 抑制剂产生更持久反应的三重抑制剂组合，并且可能受益于进一步的临床前评估。