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

Abstract

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.

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Fig. 1: AMG510 displayed variable anti-proliferative efficacy in KRASG12C-mutant cells.
Fig. 2: KrasG12C-mutant cells developed acquired resistance after continuous exposure to AMG510.
Fig. 3: Activation of RTKs rendered KRASG12C-mutant cells resistant to AMG510.
Fig. 4: Blockade of RTKs signaling potentiated the activity of AMG510 in resistant cells.
Fig. 5: Combination of the PI3Kα inhibitor with AMG510 synergistically inhibited proliferation of KRASG12C-mutant cells.
Fig. 6: Combination of CYH33 with AMG510 synergistically inhibited the growth of xenografts derived from KRASG12C-mutant cells.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82104199, 82173832 and 81973345), the Lingang Laboratory (LG202103-02-03) and Science and Technology Commission of Shanghai Municipality (22ZR1474400).

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Contributions

LHM, YXW, and WLQ conceived the study and wrote the manuscript. WLQ carried most of the experiments. HYL, JTD, and XZ performed part of the cell proliferation and Western blotting assay. YW established AMG510-acquired resistance cell lines. LX conducted part of animal experiments. LHM and YXW supervised the study. All authors proofread the manuscript and approved to submit the final manuscript.

Corresponding authors

Correspondence to Yu-xiang Wang or Ling-hua Meng.

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The authors declare no competing interests.

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Qi, Wl., Li, Hy., Wang, Y. et al. Targeting PI3Kα overcomes resistance to KRasG12C inhibitors mediated by activation of EGFR and/or IGF1R. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-01015-0

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Keywords

  • AMG510
  • KRasG12C
  • PI3K
  • drug resistance
  • combination therapy

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