Modeling Adaptive Resistance of KRAS Mutant Colorectal Cancer to MAPK Pathway Inhibitors with a Three-Dimensional Tumor Model,ACS Pharmacology & Translational Science

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Modeling Adaptive Resistance of KRAS Mutant Colorectal Cancer to MAPK Pathway Inhibitors with a Three-Dimensional Tumor Model
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-10-09 , DOI: 10.1021/acsptsci.0c00115
Pradip Shahi Thakuri ₁ , Astha Lamichhane ₁ , Sunil Singh ₁ , Megha Gupta ₂ , Gary D Luker _{3,

3,

3} , Hossein Tavana ₁

Affiliation

Single-agent drug treatment of KRAS^mut colorectal cancers is often ineffective because the activation of compensatory signaling pathways leads to drug resistance. To mimic cyclic chemotherapy treatments of patients, we showed that intermittent treatments of 3D tumor spheroids of KRAS^mut colorectal cancer cells with inhibitors of mitogen-activated protein kinase (MAPK) signaling pathway temporarily suppressed growth of spheroids. However, the efficacy of successive single-agent treatments was significantly reduced. Molecular analysis showed compensatory activation of PI3K/AKT and STAT kinases and EGFR family proteins. To overcome the adaptation of cancer cells to MAPK pathway inhibitors, we treated tumor spheroids with a combination of MEK and EGFR inhibitors. This approach significantly blocked signaling of MAPK and PI3K/AKT pathways and prevented the growth of spheroids, but it was not effective against STAT signaling. Although the combination treatment blocked the matrix invasion of DLD1 cells, additional treatments with STAT inhibitors were necessary to prevent invasiveness of HCT116 cells. Overall, our drug resistance model elucidated the mechanisms of treatment-induced growth and invasiveness of cancer cells and allowed design-driven testing and identifying of effective treatments to suppress these phenotypes.

中文翻译：

用三维肿瘤模型模拟 KRAS 突变型结直肠癌对 MAPK 通路抑制剂的适应性抗性

KRAS ^mut结直肠癌的单药药物治疗往往无效，因为代偿性信号通路的激活导致耐药性。为了模拟患者的循环化疗治疗，我们展示了 KRAS ^mut的 3D 肿瘤球体的间歇治疗具有丝裂原活化蛋白激酶 (MAPK) 信号通路抑制剂的结直肠癌细胞暂时抑制了球体的生长。然而，连续单药治疗的疗效显着降低。分子分析显示 PI3K/AKT 和 STAT 激酶和 EGFR 家族蛋白的补偿性激活。为了克服癌细胞对 MAPK 通路抑制剂的适应性，我们用 MEK 和 EGFR 抑制剂的组合处理肿瘤球体。这种方法显着阻断了 MAPK 和 PI3K/AKT 通路的信号传导并阻止了球体的生长，但它对 STAT 信号传导无效。尽管联合治疗阻止了 DLD1 细胞的基质侵袭，但需要额外的 STAT 抑制剂治疗以防止 HCT116 细胞的侵袭。总体，

更新日期：2020-12-12

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