Development of Rational Combination Therapy With Parp Inhibitors and Kinase Inhibitors In Tnbc

<p>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 <em>in vitro</em> and <em>in vivo</em>. 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 <em>in vitro</em>, 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2016

Author dc:creator

• Yu, Wen-Hsuan

Contributors dc:contributor

• Mien-Chie Hung
• Dihua Yu
• Jennifer Litton

• DNA damage and repair
• Drug resistance
• Breast cancer
• Target therapies
• Post-translational modification
• Medical Cell Biology
• Medical Molecular Biology
• Medicine and Health Sciences
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/682

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1726