Date of Graduation

8-2016

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mien-Chie Hung

Committee Member

Dihua Yu

Committee Member

Jennifer Litton

Committee Member

Paul Chiao

Committee Member

Zhimin Lu

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPi) emerge as potential targeting drugs for BRCA-deficient cancers including triple negative breast cancer (TNBC). However, it has been reported that a subgroup of patients even with BRCA mutation fails to respond to PARPi in multiple clinical trials. In this study, we identified c-Met, a tyrosine kinase, phosphorylates PARP1 at Y907 and that the phosphorylation increases PARP1 activity, thereby rendering cancer cells resistant to PARPi. The combination of c-Met inhibitors (METi) and PARPi has a synergistic effect for c-Met overexpressed TNBC in vitro and in vivo. In addition to c-Met, through functional analysis, we found casein kinase 2 (CK2) is another potential PARP1 regulator. The combination of a CK2 inhibitor (CK2i) and PARPi synergistically attenuates DNA damage repair, cell cycle, cell proliferation and xenograft tumor growth. Similar to the c-Met-PARP1 axis, CK2 interacts with PARP1 in the nucleus. Moreover, CK2 can phosphorylate PARP1 in vitro, implicating that similar to c-Met, CK2 regulates PARP1 activity through direct phosphorylation. Together, phosphorylation of PARP1 may be used as biomarkers to guide the combinational treatment of PARPi and corresponding kinase inhibitors. Our study not only has revealed a new mechanism of PARPi resistance but also provided a marker-guided combination therapeutic strategy to stratify TNBC patients who do not respond to PARPi.

Keywords

DNA damage and repair, Drug resistance, Breast cancer, Target therapies, Post-translational modification

Available for download on Wednesday, June 21, 2017

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