PROJECT SUMMARY
Anthracycline-based chemotherapy, an effective treatment for many types of cancer, has long been associated
with substantial cardiotoxicity. As one of the most commonly used anthracycline anticancer agent, doxorubicin
(DOX) induces DNA damage and subsequent cardiomyocyte apoptosis, eventually resulting in cardiomyopathy
and heart failure. Therefore, understanding the mechanisms of DOX-induced apoptosis is of paramount
importance for cardioprotection. Our published work has identified cyclin-dependent kinase 2 (CDK2) as a critical
mediator of anthracycline cardiotoxicity. Mechanistically, CDK2 augments forkhead box O1 (FOXO1)-dependent
expression of Bim, a pro-apoptotic protein indispensable for DOX-induced cardiomyocyte apoptosis. Based on
these findings, we hypothesize that cardiac CDK2 activity determines chemotherapy sensitivity (chemosensitivity)
in the heart. CDK2 is best known for its classical role in cell cycle progression in proliferating cells, and its activity
is tightly controlled by multiple proteins involved in cell cycle regulation. Since cardiomyocytes are postmitotic
cells with minimal cell cycle activity, it remains to be determined how CDK2 activity is regulated in the cardiac
settings. Interestingly, our preliminary results revealed that CDK2 was activated by CDK7, but inhibited by
retinoblastoma-like 2 (RBL2) in cardiomyocytes. In this application, we propose to tackle the roles of these cell
cycle proteins in cardiomyocyte apoptosis and cardiac chemosensitivity. This proposal has three Specific Aims:
1) Define the role of CDK7 in DOX-induced CDK2 activation and cardiomyocyte apoptosis; 2) Assess the
feasibility of the CDK7-CDK2 axis as a new drug target for DOX cardiotoxicity; and 3) Determine how RBL2
regulates CDK2 activity and cardiac DOX sensitivity. Our approach is innovative because various state-of-the-
art systems will be used, including immunocompetent mouse tumor allograft model and genetically engineered
mouse models. The novel mechanisms established in this application will have great translational potential, and
could lay the foundation for developing new cardioprotective strategies during cancer treatment.