Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors

PI3K alpha inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER thorn) patients with breast cancer. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3K alpha inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2, and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacologic inhibition of the PI3K-AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Ka inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Ka inhibition and proposes therapeutic strategies to prevent or revert this resistance. Significance: These findings show that genetic lesions of multiple negative regulators of mTORC1 could limit the efficacy of PI3Ka inhibitors in breast cancer, which may guide patient selection strategies for future clinical trials.

Automated summary

This study identified genetic lesions of multiple negative regulators of mTORC1 that may limit the efficacy of PI3Ka inhibitors in breast cancer, proposing therapeutic strategies to prevent or revert this resistance. These findings may guide patient selection strategies for future clinical trials.