Efficacious Combination Drug Treatment for Colorectal Cancer that Overcomes Resistance to KRAS G12C Inhibitors
Efficacious Combination Drug Treatment for Colorectal Cancer that Overcomes Resistance to KRAS G12C Inhibitors
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克服 KRAS G12C 抑制剂耐药性的结直肠癌有效联合药物治疗
DOI：
10.1158/1535-7163.mct-22-0411
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发表时间：
2023
影响因子：
5.7
通讯作者：
Taketo Makoto Mark
中科院分区：
文献类型：
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作者：
Matsubara Hiroyuki;Miyoshi Hiroyuki;Kakizaki Fumihiko;Morimoto Tomonori;Kawada Kenji;Yamamoto Takehito;Obama Kazutaka;Sakai Yoshiharu;Taketo Makoto Mark
组合化学的最新进展导致了针对KRAS G12C突变蛋白的抑制剂的发现。然而，其单一疗法对结直肠癌的疗效有限。因此，应探索适用于结直肠癌患者的有效联合药物，以充分受益于KRAS G12C抑制剂的治疗。在这里，我们使用患者来源的结直肠癌干细胞(PD-CRC-SC)球体培养，并显示KRAS G12C、EGFR和FGFR抑制剂的三种药物组合协同抑制携带KRAS G12C突变的结直肠癌细胞的生长。同样，KRAS G12C和SHP2抑制剂的组合也有效。重要的是，PI3K/AKT通路的激活抵消了KRAS G12C抑制的作用，而KRAS G12C抑制作用主要被PI3K抑制剂所克服。这些结果表明，评估PD-CRC-SC球体联合治疗结直肠癌的疗效可以成为寻找最佳方案的一种有前景的策略。
Recent advances in combinatorial chemistry led to the discovery of inhibitors targeting the KRAS G12C-mutant protein. However, efficacy of its monotherapy on colorectal cancer is limited. Thus, effective combination drugs should be explored for applicable patients with colorectal cancer to fully benefit from the KRAS G12C inhibitor treatment. Here we used a patient-derived colorectal cancer stem cell (PD–CRC-SC) spheroid culture and showed that three-drug combination of inhibitors against KRAS G12C, EGFR, and FGFR synergistically suppressed the growth of colorectal cancer cells carrying the KRAS G12C mutation. Likewise, a combination of KRAS G12C and SHP2 inhibitors was also effective. Importantly, activation of the PI3K/AKT pathway in heregulin-responsive colorectal cancer cells canceled out the effect of KRAS G12C inhibition, which was largely overcome by PI3K inhibitors. These results reveal that evaluating efficacy of combination therapies with PD–CRC-SC spheroids can be a promising strategy to find the best regimen for patients with colorectal cancer.