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Ref Type | Journal Article | ||||||||||||
PMID | (33685991) | ||||||||||||
Authors | Cai Y, Xu G, Wu F, Michelini F, Chan C, Qu X, Selenica P, Ladewig E, Castel P, Cheng Y, Zhao A, Jhaveri K, Toska E, Jimenez M, Jacquet Jacquet A, Tran-Dien A, Andre F, Chandarlapaty S, Reis-Filho JS, Razavi P, Scaltriti M | ||||||||||||
Title | Genomic alterations in PIK3CA-mutated breast cancer result in mTORC1 activation and limit sensitivity to PI3Kα inhibitors. | ||||||||||||
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Abstract Text | PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) breast cancer patients. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα 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 pharmacological 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 PI3Kα 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 PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance. |
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