克拉斯
西妥昔单抗
MEK抑制剂
MAPK/ERK通路
曲美替尼
表皮生长因子受体抑制剂
表皮生长因子受体
癌症研究
结直肠癌
帕尼单抗
癌症
医学
生长抑制
激酶
药理学
细胞生长
化学
生物
内科学
细胞生物学
生物化学
作者
Nao Hondo,Masato Kitazawa,Makoto Koyama,Satoshi Nakamura,Shigeo Tokumaru,Satoru Miyazaki,Masahiro Kataoka,Kai Seharada,Yuji Soejima
出处
期刊:Cancer Letters
[Elsevier]
日期:2023-07-01
卷期号:567: 216264-216264
被引量:1
标识
DOI:10.1016/j.canlet.2023.216264
摘要
The Kirsten rat sarcoma (KRAS) oncogene was “undruggable” until sotorasib, a KRASG12C selective inhibitor, was developed with promising efficacy. However, inhibition of mutant KRAS in colorectal cancer cells (CRC) is ineffective due to feedback activation of MEK/ERK downstream of KRAS. In this study, we screened for combination therapies of simultaneous inhibition to overcome sotorasib resistance using our previously developed Mix Culture Assay. We evaluated whether there was an additive effect of sotorasib administered alone and in combination with two or three drugs: trametinib, a MEK inhibitor, and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody. The MAPK pathway was reactivated in KRASG12C-mutated cell lines treated with sotorasib alone. Treatment with KRAS and MEK inhibitors suppressed the reactivation of the MAPK pathway, but upregulated EGFR expression. However, the addition of cetuximab to this combination suppressed EGFR reactivation. This three-drug combination therapy resulted in significant growth inhibition in vitro and in vivo. Our data suggest that reactive feedback may play a key role in the resistance signal in CRC. Simultaneously inhibiting KRAS, MEK, and EGFR is a potentially promising strategy for patients with KRASG12C-mutated CRC.
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