2. Academic Validation
  3. Genomic Alterations in PIK3CA-Mutated Breast Cancer Result in mTORC1 Activation and Limit the Sensitivity to PI3Kα Inhibitors

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

  • Cancer Res. 2021 May 1;81(9):2470-2480. doi: 10.1158/0008-5472.CAN-20-3232.
Yanyan Cai  # 1,  Guotai Xu  # 2 3,  Fan Wu 2,  Flavia Michelini 2 4,  Carmen Chan 2,  Xuan Qu 2,  Pier Selenica 4,  Erik Ladewig 2 5,  Pau Castel 6,  Yuanming Cheng 7,  Alison Zhao 2,  Komal Jhaveri 8,  Eneda Toska 2 9 10,  Marta Jimenez 11,  Alexandra Jacquet 11,  Alicia Tran-Dien 12 13,  Fabrice Andre 12 13 14,  Sarat Chandarlapaty 2 8,  Jorge S Reis-Filho 4,  Pedram Razavi 2 8,  Maurizio Scaltriti 1 4
Affiliations

Affiliations

  • 1 Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York. maurizio.scaltriti@astrazeneca.com caiy@mskcc.org.
  • 2 Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 National Institute of Biological Sciences (NIBS), Beijing, China.
  • 4 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 5 Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 6 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
  • 7 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 8 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 9 Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 10 Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, Maryland.
  • 11 Unicancer, Paris, France.
  • 12 INSERM UMR981 and Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
  • 13 Université Paris Saclay, Le Kremlin-Bicetre, France.
  • 14 Department of Medical Oncology, Gustave Roussy, Université Paris Saclay, Villejuif, France.
  • # Contributed equally.
PMID: 33685991 DOI: 10.1158/0008-5472.CAN-20-3232
Abstract

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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