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Targeting PI3K alpha overcomes resistance to KRas(G12C) inhibitors mediated by activation of EGFR and/or IGF1R

文献类型：期刊论文

作者Qi, Wei-liang1,2,3; Li, Hui-yu1,2; Wang, Yi1; Xu, Lan1; Deng, Jie-ting4; Zhang, Xi1; Wang, Yu-xiang1; Meng, Ling-hua1,2,4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2022-11-21
页码12
关键词AMG510 KRas(G12C) PI3K drug resistance combination therapy
ISSN号1671-4083
DOI10.1038/s41401-022-01015-0
通讯作者Wang, Yu-xiang(yxwang@simm.ac.cn) ; Meng, Ling-hua(lhmeng@simm.ac.cn)
英文摘要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.
WOS关键词KRAS G12C ; KRYSTAL-1 ACTIVITY ; SCREENING REVEALS ; ADAGRASIB MRTX849 ; AMG 510 ; RAS ; CARCINOMAS ; GTPASE ; SAFETY
资助项目National Natural Science Foundation of China[82104199] ; National Natural Science Foundation of China[82173832] ; National Natural Science Foundation of China[81973345] ; National Natural Science Foundation of China[LG202103-02-03] ; Science and Technology Commission of Shanghai Municipality[22ZR1474400]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000886173300001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/304548]  
专题中国科学院上海药物研究所
通讯作者Wang, Yu-xiang; Meng, Ling-hua
作者单位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
推荐引用方式
GB/T 7714		 Qi, Wei-liang,Li, Hui-yu,Wang, Yi,et al. Targeting PI3K alpha overcomes resistance to KRas(G12C) inhibitors mediated by activation of EGFR and/or IGF1R[J]. ACTA PHARMACOLOGICA SINICA,2022:12.
APA Qi, Wei-liang.,Li, Hui-yu.,Wang, Yi.,Xu, Lan.,Deng, Jie-ting.,...&Meng, Ling-hua.(2022).Targeting PI3K alpha overcomes resistance to KRas(G12C) inhibitors mediated by activation of EGFR and/or IGF1R.ACTA PHARMACOLOGICA SINICA,12.
MLA Qi, Wei-liang,et al."Targeting PI3K alpha overcomes resistance to KRas(G12C) inhibitors mediated by activation of EGFR and/or IGF1R".ACTA PHARMACOLOGICA SINICA (2022):12.

入库方式： OAI收割

来源：上海药物研究所

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