Reference Detail

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 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 the Sensitivity to PI3Kα Inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	81	9	2021 May 01	2470-2480	Cancer Res

URL

Abstract Text

PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER + ) 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 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 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 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. SIGNIFICANCE: These findings show that genetic lesions of multiple negative regulators of mTORC1 could limit the efficacy of PI3Kα inhibitors in breast cancer, which may guide patient selection strategies for future clinical trials.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA act mut TSC1 del	estrogen-receptor positive breast cancer	resistant	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cells with knockout of TSC1 demonstrated resistance to growth inhibition by Piqray (alpelisib) in culture, and decreased sensitivity to Piqray (alpelisib) in a cell line xenograft model (PMID: 33685991).	33685991
PIK3CA act mut TSC1 del	estrogen-receptor positive breast cancer	resistant	Taselisib	Preclinical - Cell culture	Actionable	In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cell lines with knockout of TSC1 were resistant to treatment with Taselisib (GDC-0032) in culture (PMID: 33685991).	33685991
PIK3CA act mut TSC2 del	estrogen-receptor positive breast cancer	resistant	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cell lines with knockout of TSC2 were resistant to treatment with Piqray (alpelisib) in culture (PMID: 33685991).	33685991
PIK3CA act mut TSC2 del	estrogen-receptor positive breast cancer	resistant	Taselisib	Preclinical - Cell culture	Actionable	In a preclinical study, PIK3CA-mutant, ESR1 (ER)-positive breast cancer cell lines with knockout of TSC2 were resistant to treatment with Taselisib (GDC-0032) in culture (PMID: 33685991).	33685991