The clinical effectiveness of KRASG12C inhibitors (G12Ci) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. Here, we identified targeting proximal receptor tyrosine kinase (RTK) signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment. SOS1i enhanced the efficacy of G12Ci and limited rebound RTK/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels. G12Ci drug tolerant persister (DTP) cells showed up to a 3-fold enrichment of tumor initiating cells (TIC), suggestive of a sanctuary population of G12Ci resistant cells. SOS1i re-sensitized DTPs to G12Ci and inhibited G12C-induced TIC enrichment. Co-mutation of the tumor suppressor KEAP1 limited the clinical effectiveness of G12Ci, and KEAP1 and STK11 deletion increased TIC frequency and accelerated the development of acquired resistance to G12Ci, consistent with clinical G12Ci resistance seen with these co-mutations. Treatment with SOS1i both delayed acquired G12Ci resistance and limited the total number of resistant colonies regardless of KEAP1 and STK11 mutational status. Together, these data suggest that targeting SOS1 could be an effective strategy to both enhance G12Ci efficacy and prevent G12Ci resistance regardless of co-mutations.

中文翻译：

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SOS1 抑制增强 KRASG12C 抑制剂的疗效并延缓肺腺癌的耐药性


KRASG12C抑制剂 （G12Ci） 的临床有效性受到内在和获得性耐药的限制，因此需要开发联合方法。在这里，我们使用 SOS1 抑制剂 （SOS1i） BI-3406 确定了靶向近端受体酪氨酸激酶 （RTK） 信号传导，作为改善对 G12Ci 治疗反应的策略。SOS1i 增强了 G12Ci 和有限反弹 RTK/ERK 信号转导克服内在/适应性抵抗的功效，但这种作用受 SOS2 蛋白水平的调节。G12Ci 药物耐受持久性 （DTP） 细胞显示肿瘤起始细胞 （TIC） 富集高达 3 倍，表明 G12Ci 耐药细胞的庇护群。SOS1i 使 DTP 对 G12Ci 再敏感并抑制 G12C 诱导的 TIC 富集。抑癌基因 KEAP1 的共突变限制了 G12Ci 的临床疗效，KEAP1 和 STK11 缺失增加了 TIC 频率并加速了对 G12Ci 的获得性耐药的发展，这与这些共突变的临床 G12Ci 耐药一致。SOS1i 治疗既延迟了获得性 G12Ci 耐药，又限制了耐药集落的总数，无论 KEAP1 和 STK11 突变状态如何。总之，这些数据表明，靶向 SOS1 可能是增强 G12Ci 疗效和防止 G12Ci 耐药的有效策略，无论共突变如何。