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.
","abstract_html":"<p>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 (<em>BRCA</em><sup>m</sup>). 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.</p>","abstract_has_math":false,"creators":["CHEN, MEI-KUANG","https://orcid.org/0000-0001-8027-8990
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Dihua Yu","Mien-Chie Hung","Jennifer L. Litton"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-05-01T07:00:00Z","date_published":"2020-05-01T07:00:00Z","updated_at":"2026-07-24T05:48:59Z","subjects":["talazoparib","olaparib","PARP trapping","kinase","RTK","Cancer Biology","Medicine and Health Sciences","Translational Medical Research"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/998","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dihua Yu","Mien-Chie Hung","Jennifer L. Litton"]},{"key":"dc:creator","label":"Author","values":["CHEN, MEI-KUANG","https://orcid.org/0000-0001-8027-8990
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"]},{"key":"dc:title","label":"Title","values":["Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer"]}]}],"canonical_facts":{"dc:contributor":["Dihua Yu","Mien-Chie Hung","Jennifer L. Litton"],"dc:creator":["CHEN, MEI-KUANG","https://orcid.org/0000-0001-8027-8990
"],"dc:date.available":["2021-04-26T07:00:00Z"],"dc:description.abstract":["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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/998"],"dc:subject":["talazoparib","olaparib","PARP trapping","kinase","RTK","Cancer Biology","Medicine and Health Sciences","Translational Medical Research"],"dc:title":["Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:48:59Z"}