Author ORCID Identifier
Date of Graduation
8-2019
Document Type
Thesis (MS)
Program Affiliation
Cancer Biology
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Jeffrey Chang (on-site)
Committee Member
Mien-Chie Hung
Committee Member
Bin Wang
Committee Member
Jennifer Litton
Committee Member
Stacy Moulder
Committee Member
Kenneth Hess
Abstract
Triple-negative breast cancer is associated with a poor prognosis and treatment options are limited. The Poly (ADP-ribose) polymerase (PARP) inhibitors, olaparib and talazoparib, were recently approved for metastatic breast cancer (including triple-negative breast cancer) in patients with a germline BRCA1/2 mutation. Despite impressive response rates of ~60%, the prolongation in median progression-free survival with PARP inhibitors is modest, suggesting the emergence of resistance. We previously demonstrated that c-MET contributes to intrinsic resistance to PARP inhibitors in triple-negative breast cancer. However, whether c-MET plays a role in acquired resistance to PARP inhibitors in triple-negative breast cancer remains unclear. Here, we show that phospho-c-MET expression is higher in PARP inhibitor-resistant triple-negative breast cancer cells and the combination of talazoparib and crizotinib (multi-kinase inhibitor that inhibits c-MET) results in synergistic inhibition of cellular proliferation in PARP inhibitor-resistant cells. However, depleting c-MET in PARP inhibitor resistant cells had limited effect on talazoparib sensitivity. Notably, we found that c-MET interacts with the epidermal growth factor receptor (EGFR) in PARP inhibitor-resistant triple-negative breast cancer cells, potentially explaining the limited effect of c-MET depletion alone on talazoparib sensitivity. Together, these data suggest that the combination of c-MET, EGFR and PARP inhibition should be explored in future studies.
Keywords
Triple-negative breast cancer, PARP inhibitors, resistance, c-MET, EGFR