Abstract B104: Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations

Molecular alterations in the PI3K/AKT/mTOR pathway occur frequently in estrogen receptor-positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2-negative (HER2-negative) advanced or metastatic breast cancer (MBC) are often treated with palbociclib, an FDA approved CDK4/6 inhibitor, in combination with endocrine therapy. In clinical studies (NCT01942135), the combination of fulvestrant plus palbociclib was associated with improved progression-free survival compared with fulvestrant plus placebo, irrespective of PIK3CA mutational status. The purpose of this study is to identify synthetic lethality partner that can be targeted in combination with palbociclib to improve its therapeutic response. We demonstrate that the in vitro efficacy of CDK4/6 inhibitor is reduced in the presence of PIK3CA/AKT1 mutations using ER-positive isogenic breast cancer cell lines. Utilizing a shRNA library screen targeting cancer related human kinases, we identified that genomic suppression of discoidin domain receptor 1 (DDR1), a tyrosine kinase active in various cancers, is synthetic lethal with palbociclib. Performing sulforhodamine B (SRB) proliferation assay, DDR1 knockdown by shRNA significantly reduced growth of PIK3CA/AKT1 mutant as well as wild type ER-positive cell lines. In addition, DDR1 pharmacological inhibitor, 7rh benzamide, activated the P53/P21 pathway and enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Likewise, we found that combined treatment of palbociclib and 7rh further induced cell cycle arrest through decreasing G2-M phase population and reducing FoxM1 and Rb phosphorylation in mutant cell lines. Our data indicate that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be an effective rational strategy approach for targeted therapy of ER-positive, HER2-negative breast cancer harboring PIK3CA/AKT1 mutations. Citation Format: Maryam Shariati, Christopher A Bristow, Alessandro Carugo, Tim Heffernan, Xiaofeng Zheng, Michael D Peoples, Debu Tripathy, Funda Meric-Bernstam. Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B104. doi:10.1158/1535-7163.TARG-19-B104