Author ORCID Identifier

Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dihua Yu

Committee Member

Mien-Chie Hung

Committee Member

Jennifer L. Litton

Committee Member

Shiaw-Yih Lin

Committee Member

Bin Wang

Committee Member

Jeffrey T. Chang

Committee Member

Paul J. Chiao


Leveraging compromised DNA damage repair (DDR) pathways commonly found in tumor cells, a classic strategy in cancer therapy is inducing excessive DNA damage to cause cancer cell death. Small molecule poly(ADP-ribose) polymerase (PARP) inhibitors (PARP-is) have been approved for clinical use in treating breast cancer and ovarian cancer patients bearing DDR-deficient tumors with mutations in breast cancer susceptibility genes (BRCAm). However, accumulating evidences show that both intrinsic and acquired resistances to PARP-is exist in clinic and pre-clinical animal models. Therefore, I developed panels of cells with acquired PARP-is resistance from PARP-is-sensitive triple negative breast cancer (TNBC) cell lines, and used these cells to screen for common traits that can be targeted with feasible therapeutic agent combinations to overcome PARP-is resistance. Since TNBC lacks of effective targeted therapy so far, I focused on developing and using a panel of PARP-is-resistant TNBC cells in this study. Among the molecular mechanisms known contribute to PARP-is resistance, oncogenic kinase activations, including several hyper-activated receptor tyrosine kinases (RTKs), are involved in enhancing DNA damage repair and decreasing affinity of PARP-is to PARP1. Among the candidate RTKs, MET has more small molecules inhibitors that can target it, and thus, my colleagues and I made it a priority in investigating synergism between MET inhibitor and PARP inhibitor in multiple cancer types and demonstrated that combinations of PARP-is and MET inhibitors possess moderate to strong synergism in the different cancer types we studied. In this thesis, I systematically screened for activated RTKs as common traits in the PARP-is-resistant cells I developed. Through non-biased antibody array screening, I found MET phosphorylation is also high in the TNBC cells with acquired PARP-is resistance. However, there are several activated RTKs have higher prevalence than MET, including FGFR, EGFR and IGF1R. Therefore, in this thesis, I extended my study from MET to other candidate RTKs and demonstrated that MET is not the only RTK contribute to PARP-i-resistance in TNBC, and I found that RTKs have different working mechanisms toward PARP-i-resistance. In conclusion, RTKs contribute to PARP-i-resistance through multiple mechanisms and it is worthwhile to investigate these mechanisms to unveil more targeted therapeutic strategies for cancer patients with PARP-i-resistance.


talazoparib, olaparib, PARP trapping, kinase, RTK