Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in a panel of hormonally diverse cell lines. Additionally, we investigated dual inhibition in triple-negative breast cancer (TNBC) and tamoxifen resistant models. Both of which do not currently have targeted therapy available. Our results (in TNBC cells) indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In summary, the results from this study provide a unique perspective into the utility of a novel dual inhibition strategy for targeting TNBCs.
","abstract_html":"<p>Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in a panel of hormonally diverse cell lines. Additionally, we investigated dual inhibition in triple-negative breast cancer (TNBC) and tamoxifen resistant models. Both of which do not currently have targeted therapy available. Our results (in TNBC cells) indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In summary, the results from this study provide a unique perspective into the utility of a novel dual inhibition strategy for targeting TNBCs.</p>","abstract_has_math":false,"creators":["Wright, Thomas Douglas"],"institution":null,"degree_name":"PhD","degree_level":"One-year Embargo","degree_discipline":"Pharmacology","degree_department":null,"school":null,"contributors":["Jane E. Cavanaugh","Wilson S. Meng","Lauren O’Donnell","Patrick T. Flaherty","Paula A. Witt-Enderby","David A. Johnson"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019-08-10T07:00:00Z","date_published":"2019-08-10T07:00:00Z","updated_at":"2026-07-24T02:10:50Z","subjects":["PI3K/Akt","MEK5/ERK5","Synergy","Triple-negative breast cancer","Medicinal and Pharmaceutical Chemistry","Other Pharmacy and Pharmaceutical Sciences","Pharmacology"],"languages":["United States"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://dsc.duq.edu/etd/1822","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Jane E. Cavanaugh","Wilson S. Meng","Lauren O’Donnell","Patrick T. Flaherty","Paula A. Witt-Enderby","David A. Johnson"]},{"key":"dc:creator","label":"Author","values":["Wright, Thomas Douglas"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2020-08-10T07:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pharmacology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["One-year Embargo"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["PI3K/Akt","MEK5/ERK5","Synergy","Triple-negative breast cancer","Medicinal and Pharmaceutical Chemistry","Other Pharmacy and Pharmaceutical Sciences","Pharmacology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["United States"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://dsc.duq.edu/etd/1822"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in a panel of hormonally diverse cell lines. Additionally, we investigated dual inhibition in triple-negative breast cancer (TNBC) and tamoxifen resistant models. Both of which do not currently have targeted therapy available. Our results (in TNBC cells) indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In summary, the results from this study provide a unique perspective into the utility of a novel dual inhibition strategy for targeting TNBCs.
"]},{"key":"dc:title","label":"Title","values":["Dual Inhibition of the PI3K/Akt and MEK5/ERK5 Pathways for the Treatment of Breast Cancer"]}]}],"canonical_facts":{"dc:contributor":["Jane E. Cavanaugh","Wilson S. Meng","Lauren O’Donnell","Patrick T. Flaherty","Paula A. Witt-Enderby","David A. Johnson"],"dc:creator":["Wright, Thomas Douglas"],"dc:date.available":["2020-08-10T07:00:00Z"],"dc:description.abstract":["Breast cancer is a heterogeneous disease state with several challenging frontiers. In particular, aberrations in the Phosphoinositide-3-kinase (PI3K) and Mitogen Activated Protein Kinase (MAPK) pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. New evidence suggests that MEK5/ERK5, a member of the MAPK family, is a crucial component in the proliferation and survival of several aggressive cancers. We hypothesize that inhibiting both PI3K/Akt and MEK5/ERK5 pathways will decrease cell viability while maintaining limited collateral toxicity. In this study, we examined the effects of dual inhibition of PI3K/Akt and MEK5/ERK5 in a panel of hormonally diverse cell lines. Additionally, we investigated dual inhibition in triple-negative breast cancer (TNBC) and tamoxifen resistant models. Both of which do not currently have targeted therapy available. Our results (in TNBC cells) indicate that the dual inhibition strategy was more effective than single inhibition due to the loss of crosstalk between the two pathways. In summary, the results from this study provide a unique perspective into the utility of a novel dual inhibition strategy for targeting TNBCs.
"],"dc:identifier":["https://dsc.duq.edu/etd/1822"],"dc:language":["United States"],"dc:subject":["PI3K/Akt","MEK5/ERK5","Synergy","Triple-negative breast cancer","Medicinal and Pharmaceutical Chemistry","Other Pharmacy and Pharmaceutical Sciences","Pharmacology"],"dc:title":["Dual Inhibition of the PI3K/Akt and MEK5/ERK5 Pathways for the Treatment of Breast Cancer"],"thesis:degree_discipline":["Pharmacology"],"thesis:degree_level":["One-year Embargo"],"thesis:degree_name":["PhD"]},"updated_at":"2026-07-24T02:10:50Z"}