Matsubara Hiroyuki, Miyoshi Hiroyuki, Kakizaki Fumihiko, Morimoto Tomonori, Kawada Kenji, Yamamoto Takehito, Obama Kazutaka, Sakai Yoshiharu, Taketo Makoto Mark
Colon Cancer Project, Kyoto University Hospital-iACT, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Mol Cancer Ther. 2023 Apr 3;22(4):529-538. doi: 10.1158/1535-7163.MCT-22-0411.
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.
组合化学的最新进展促使人们发现了针对KRAS G12C突变蛋白的抑制剂。然而，其单药治疗对结直肠癌的疗效有限。因此，应探索有效的联合用药方案，以使适用的结直肠癌患者能够充分受益于KRAS G12C抑制剂治疗。在此，我们使用患者来源的结直肠癌干细胞（PD-CRC-SC）球体培养模型，结果表明，针对KRAS G12C、EGFR和FGFR的三种药物联合使用可协同抑制携带KRAS G12C突变的结直肠癌细胞的生长。同样，KRAS G12C抑制剂与SHP2抑制剂联合使用也有效。重要的是，在此调节蛋白反应性结直肠癌细胞中，PI3K/AKT通路的激活抵消了KRAS G12C抑制的作用，而PI3K抑制剂在很大程度上克服了这一问题。这些结果表明，用PD-CRC-SC球体评估联合治疗的疗效可能是为结直肠癌患者找到最佳治疗方案的一种有前景的策略。
