Author ORCID Identifier

https://orcid.org/0000-0002-0809-0851

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

Available for download on Saturday, June 20, 2020

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