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

Wei-liang Qi1,2,3, Hui-yu Li1,2, Yi Wang1, Lan Xu1, Jie-ting Deng4, Xi Zhang1, Yu-xiang Wang1, Ling-hua Meng1,2,4
1 Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.501 Haike Road, Shanghai 201203, China
2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
3 College of Pharmacy, Nanchang University, No. 461, Bayi Road, Nanchang 330006, China
4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
Correspondence to: Yu-xiang Wang:, Ling-hua Meng:,
DOI: 10.1038/s41401-022-01015-0
Received: 4 July 2022
Accepted: 18 October 2022
Advance online: 21 November 2022


Although several KRasG12C inhibitors have displayed promising efficacy in clinical settings, acquired resistance developed rapidly and circumvented the activity of KRasG12C inhibitors. To explore the mechanism rendering acquired resistance to KRasG12C inhibitors, we established a series of KRASG12C-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 KRASG12C-mutant cells. Concurrently treatment of a novel PI3Kα inhibitor CYH33 with AMG510 exhibited a synergistic effect against parental and resistant KRASG12C-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 KRasG12C inhibitors and provided a mechanistic rationale to combine PI3Kα inhibitors with KRasG12C inhibitors for therapy of KRASG12C-mutant cancers in future clinical trials.
Keywords: AMG510; KRasG12C; PI3K; drug resistance; combination therapy

Article Options

Download Citation

Cited times in Scopus