Role of C-Met and Egfr In Acquired Resistance to Parp Inhibitors In Triple-Negative Breast Cancer

<p>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 <em>BRCA1/2</em> 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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2019

Authors dc:creator

• Yam, Clinton
• <p><a href="https://orcid.org/0000-0002-0809-0851?lang=en" target="_blank">https://orcid.org/0000-0002-0809-0851</a></p>

Contributors dc:contributor

• Jeffrey Chang (on-site)
• Mien-Chie Hung
• Bin Wang

• Triple-negative breast cancer
• PARP inhibitors
• resistance
• c-MET
• EGFR
• Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/952

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1997