TY - JOUR
T1 - Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations
AU - Shariati, Maryam
AU - Evans, Kurt W.
AU - Zheng, Xiaofeng
AU - Bristow, Christopher A.
AU - Ng, Patrick Kwok Shing
AU - Rizvi, Yasmeen Q.
AU - Tapia, Coya
AU - Yang, Fei
AU - Carugo, Alessandro
AU - Heffernan, Timothy P.
AU - Peoples, Michael D.
AU - Tripathy, Debu
AU - Meric-Bernstam, Funda
N1 - Funding Information:
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.
Funding Information:
Conflict of interest 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.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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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U2 - 10.1038/s41388-021-01819-0
DO - 10.1038/s41388-021-01819-0
M3 - Article
C2 - 34108622
AN - SCOPUS:85107438543
SN - 0950-9232
VL - 40
SP - 4425
EP - 4439
JO - Oncogene
JF - Oncogene
IS - 26
ER -