Advisor(s)
Hind Lal
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Cellular and Molecular Physiology
Date of Award
9-11-2025
Abstract
Targeted cancer therapies are known to cause cardiovascular (CV) complications in human patients. Agents such as osimertinib, a tyrosine kinase inhibitor (TKI), as well as immune checkpoint inhibitors (ICIs) have been demonstrated to induce severe cardiotoxicities, including heart failure and myocarditis. Nevertheless, the mechanisms of TKIs and ICIs-induced cardiotoxicity remain poorly understood. Herein, we developed the first in vivo preclinical model of osimertinib-induced cardiotoxicity using a transverse aortic constriction (TAC) mouse model. Osimertinib-treated mice displayed severe cardiac dysfunction, elevated markers of heart failure and fibrosis, and failed to undergo compensatory hypertrophic remodeling, resulting in cardiomyocyte death. Mechanistically, we identified suppression of ERK/AKT prosurvival signaling, mitochondrial dysfunction, and activation of Bax/Bcl-xl apoptosis pathway. FDA-approved HDAC inhibitor Vorinostat (SAHA), restored cardiac function and cell survival while improving osimertinib’s efficacy in non-small cell lung cancer (NSCLC)-derived PC9 cells. In a separate set of studies, we examined ICIs-associated myocarditis employing a myeloid-specific programmed death-ligand (PD-L1) knockout (KO) mice. Deletion of PD-L1 led to early-onset cardiac dysfunction, systemic inflammation, increased infiltration of CCR2+ pro-inflammatory macrophages, and enhanced T cell activation, revealing a critical immunoregulatory role for myeloid PD-L1 in maintaining cardiac homeostasis. Our findings define the mechanisms of cardiotoxicity induced by targeted therapies and highlight histone deacetylase (HDAC) inhibitions and myeloid-specific immune modulation as potential targeted strategies to mitigate treatment-related cardiac events.
ProQuest ID
Recommended Citation
Toro-Cora, Angelica, "Mechanism Of Targeted Cancer Therapeutics-Induced Cardiotoxicity" (2025). All ETDs from UAB. 7339.
https://digitalcommons.library.uab.edu/etd-collection/7339
