Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R

被引:9
作者
Qi, Wei-liang [1 ,2 ,3 ]
Li, Hui-yu [1 ,2 ]
Wang, Yi [1 ]
Xu, Lan [1 ]
Deng, Jie-ting [4 ]
Zhang, Xi [1 ]
Wang, Yu-xiang [1 ]
Meng, Ling-hua [1 ,2 ,4 ]
机构
[1] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, 501 Haike Rd, Shanghai 201203, Peoples R China
[2] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
[3] Nanchang Univ, Coll Pharm, 461 Bayi Rd, Nanchang 330006, Jiangxi, Peoples R China
[4] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
基金
中国国家自然科学基金;
关键词
AMG510; KRas(G12C); PI3K; drug resistance; combination therapy; KRAS G12C; KRYSTAL-1; ACTIVITY; SCREENING REVEALS; ADAGRASIB MRTX849; AMG; 510; CARCINOMAS; GTPASE; SAFETY;
D O I
10.1038/s41401-022-01015-0
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Although several KRas(G12C) inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRas(G12C) inhibitors. To explore the mechanism rendering acquired resistance to KRas(G12C) inhibitors, we established a series of KRAS(G12C)-mutant cells with acquired resistance to AMG510. We found that differential activation of receptor tyrosine kinases (RTKs) especially EGFR or IGF1R rendered resistance to AMG510 in different cellular contexts by maintaining the activation of MAPK and PI3K signaling. Simultaneous inhibition of EGFR and IGF1R restored sensitivity to AMG510 in resistant cells. PI3K integrates signals from multiple RTKs and the level of phosphorylated AKT was revealed to negatively correlate with the anti-proliferative activity of AMG510 in KRAS(G12C)-mutant cells. Concurrently treatment of a novel PI3K alpha inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRAS(G12C)-mutant cells in vitro and in vivo, which was accompanied with concomitant inhibition of AKT and MAPK signaling. Taken together, these findings revealed the potential mechanism rendering acquired resistance to KRas(G12C) inhibitors and provided a mechanistic rationale to combine PI3K alpha inhibitors with KRas(G12C) inhibitors for therapy of KRAS(G12C)-mutant cancers in future clinical trials.
引用
收藏
页码:1083 / 1094
页数:12
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