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Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations

Abstract

Molecular alterations in the PI3K/AKT pathway occur frequently in hormone receptor-positive breast tumors. Patients with ER-positive, HER2-negative metastatic breast cancer are often treated with CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy. Although this is an effective regimen, most patients ultimately progress. The purpose of this study was identifying synthetic lethality partners that can enhance palbociclib’s antitumor efficacy in the presence of PIK3CA/AKT1 mutations. We utilized a barcoded shRNA library to determine critical targets for survival in isogenic MCF7 cells with PIK3CA/AKT1 mutations. We demonstrated that the efficacy of palbociclib is reduced in the presence of PIK3CA/AKT1 mutations. We also identified that the downregulation of discoidin domain receptor 1 (DDR1) is synthetically lethal with palbociclib. DDR1 knockdown and DDR1 pharmacological inhibitor decreased cell growth and inhibited cell cycle progression in all cell lines, while enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest in PIK3CA/AKT1 mutant cell lines. In vivo, 7rh significantly enhanced palbociclib’s antitumor efficacy. Our data indicates that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be effective strategy for targeted therapy of ER-positive, HER2-negative breast cancers with PI3K pathway activation.

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Fig. 1: PIK3CA and AKT1 mutations conferred growth advantage and reduced the sensitivity of palbociclib.
Fig. 2: shRNA library screening identified DDR1 as a candidate synthetic lethal partner for palbociclib in both PIK3CA and AKT1 mutant cell lines.
Fig. 3: Silencing DDR1 sensitized PIK3CA and AKT1 mutants cells to palbociclib treatment.
Fig. 4: Inhibition of DDR1 with 7rh sensitized PIK3CA and AKT1 mutants cells to palbociclib treatment in vitro.
Fig. 5: Dual inhibition of DDR1 and CDK4/6 decreased tumor growth of PIK3CA mutant cells in vivo.

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Acknowledgements

We thank Visual Art at the University of Texas, MD Anderson Cancer Center for assistance with the illustration in Fig. 2A. We also thank Susanna Brisendine for administrative assistance.

Funding

This work was funded in part by the Nellie B. Connally Breast Cancer Research Endowment, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, the MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core. The MD Anderson Reverse Phase Protein Array Core Facility and Histology, Pathology, and Imaging Core were funded by the Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.

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Correspondence to Funda Meric-Bernstam.

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MS, KWE, XZ, CA, PKS Ng, YQR, FY, AC, and MDP declare no potential conflict of interest. CT is an employee of Epizyme Inc., and performed contract work for Armo Bioscience. TPH reports personal fees and stock ownership from Cullgen Inc. DT reports receiving commercial research grants from Novartis, Polyphor. He also served as a consultant for Pfizer, AstraZeneca, GlaxoSmithKline, Genomic Heath, OncoPep. FMB reports receiving commercial research grants from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co. She also served as a consultant for AbbVie, Aduro BioTech Inc., DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceutical, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, and Zymeworks. In addition, she has served on advisory committees for Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals and Zentalis.

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Shariati, M., Evans, K.W., Zheng, X. et al. Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations. Oncogene (2021). https://doi.org/10.1038/s41388-021-01819-0

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