Key result
PI3K p110α inhibition slows tumor progression but exacerbates chemotherapy-induced cardiotoxicity.
Why the study?
Cancer therapies can cause unintended cardiotoxicity because growth factor pathways critical for tumor growth, such as PI3K(p110alpha), also maintain normal heart function.
Understanding the dual role of PI3K(p110α) is crucial for developing cancer therapies that minimize cardiotoxicity, as inhibiting this pathway can halt tumor growth but simultaneously damage heart muscle.
Shared pathways between cancer and cardiac signaling warrant integrated cardio-oncology monitoring; leaves open targeted prevention strategies in survivors.
The development of new cancer therapies with greater efficacy has reduced mortality for many cancers, as well as improving survivorship. However, for some cancer treatments, this has uncovered unintended cardiotoxicity during or after treatment, and cardiovascular disease has emerged as a leading cause of mortality in some cancer survivors. This may occur because many of the same growth factor signaling pathways that lead to tumor growth are also critical for maintaining normal heart function. A class IA phosphoinositide 3-kinase, PI3K(p110 α ), is a critical regulator of normal heart biology, function and exercise-induced cardiac protection, but is also mutated/increased in some cancer types. In this review, we discuss the dual role of PI3K(p110 α ) signaling in cancer and the heart. The paradox being, that inhibiting PI3K(p110 α ) in a setting of some cancer types would be beneficial for halting/slowing tumor progression but could also damage heart muscle cells. Exercise and PI3K(p110 α ) has beneficial effects on heart function via cardiac excitation and contraction, mitochondrial adaptations, cellular stress responses to promote survival, preventing cell death and cardiac fibrosis. We contrast this to the chemotherapy, doxorubicin, which is crucial for the treatment of many cancers but negatively impacts many of the beneficial effects of exercise and PI3K(p110 α ). Doxorubicin's clinical efficacy is limited by dose-dependent cardiotoxicity including cardiomyopathy, atrial fibrillation, and heart failure. A summary of reported cardiovascular effects in clinical trials using PI3K inhibitors is also provided. Finally, we discuss some of the current and emerging approaches to mitigate cancer therapy-induced cardiotoxicity including pharmacological interventions, gene therapy and dietary approaches based on preclinical studies. Advances in the field are likely to come from continued refinement of cardiotoxicity models, the investigation of targeting molecular pathways and targets with relevant primary endpoints for both cancer and heart function, and collaborative research with discovery/preclinical scientists and clinicians.
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Belkin et al. (2026) conducted a review in Chemotherapy-induced cardiotoxicity. PI3K inhibitors and Anthracyclines was evaluated. PI3K(p110α) signaling plays a critical dual role, where its inhibition slows tumor progression but exacerbates chemotherapy-induced cardiotoxicity, necessitating novel cardioprotective strategies.
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