PROJECT SUMMARYThere has been a significant decline in cancer related mortality partly due to the emergence of moleculartargeted therapies. Unfortunately the success of these drugs including tyrosine kinase inhibitors (TKIs) has beentempered by a concomitant rise in the prevalence of cancer therapies-related cardiotoxicity. Ponatinib a currentlyFDA-approved third-generation TKI is used to treat chronic myeloid leukemia (CML) patients carrying thegatekeeper mutation breakpoint cluster region-Abelson (BCR-ABL) T315I. Despite its effectiveness aconsiderable number of patients receiving ponatinib suffers from various cardiac complications. Several studieshave linked ponatinib-induced cardiotoxicity to impaired pro-survival signaling pathways leading to cell death.However the molecular signaling pathways leading to these events remain obscure and a better understandingof how cardiomyocytes respond to ponatinib may provide new insights into novel mitigation therapies. The heartmust adapt to stress conditions that occur as a result of intracellular or extracellular factors. The integrated stressresponse (ISR) is one of the circuits responding to stress and serving to restore proteostasis by regulating proteinsynthesis although prolonged ISR activation leads to cell death. Whether the ISR is activated and plays aprotective or detrimental role in ponatinib-induced cardiotoxicity are largely unknown and may represent anamenable therapeutic target which will be the focus of my current proposal. My preliminary data suggests thatponatinib causes mitochondrial dysfunction in human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs). Interestingly mitochondrial damage appears to trigger activation of the ISR and is mediated by akinase called general control non-repressed 2 (GCN2). I also found that inhibition of the ISR using a novel smallmolecule called ISR inhibitor (ISRIB) successfully blunted the cardiotoxic effects of ponatinib both in vitro and invivo. Hence the central hypothesis of my proposal is that the ISR pathway which is activated upon sensingmitochondrial damage plays a pivotal role in mediating ponatinib-induced cardiotoxicity. Aim 1 will investigatewhether activation of GCN2 couples mitochondrial damage to ISR activation upon impaired mitochondrialreactive oxygen species (ROS) and adenosine triphosphate (ATP) level. Aim 2 will assess whether ponatinibinduces apoptosis and cardiac dysfunction through the GCN2/eIF2/ATF4 axis. Lastly aim 3 will explore whetherpharmacological suppression of the ISR even after the onset of ponatinib-induced cardiotoxicity remainscardioprotective without compromising the efficacy of ponatinib against tumor cells. Taken together at theconclusion of these studies we will have significantly expanded our knowledge by which how ponatinib-inducedmitochondrial dysfunction is sensed to trigger the ISR; whether this activation contributes to cardiac pathology;and if crosstalk between these two pathways can be targeted as a therapeutic avenue to mitigate ponatinib-induced cardiotoxicity clinically.