PT-015 - TRANSPORT AND KINASE DEPENDENT REGULATION OF TYROSINE KINASE INHIBITOR INDUCED CARDIOTOXICITY.

V. Xu¹, K. Pasquariello¹, L. Karzoun¹, A. Sparreboom², J. Sprowl¹; ¹University at Buffalo, Buffalo, NY, USA, ²The Ohio State University, Columbus, OH, USA.

Background: Osimertinib is an epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor (TKI) used to treat non-small cell lung cancer. Unfortunately, many patients using osimertinib can succumb to devastating cardiotoxic symptoms. Despite this life-threatening side effect, the factors contributing to osimertinib cardiotoxicity are unknown. This is largely due to lack of models capable of measuring this adverse event. We hypothesize that osimertinib reduces cardiomyocyte viability and that this event can be influenced by alteration of drug transport or off-target kinase activity.

Methods: Viability of induced pluripotent stem cell (iPSC) or AC16 cardiomyocytes was measured after a daily dose of osimertinib (0.1 – 10 μM), other EGFR-targeting TKIs, or vehicle alone for 24 hours or 2 weeks using the Cell Titer-Glo Luminescent Assay. AC16 sensitivity to osimertinib was also measured in the presence or absence of cimetidine, or in the presence or absence of IGF1R- or MATE1-targeting siRNAs. Cellular accumulation of 14C-osimertinib was measured in MATE1 overexpressing or vector control HEK293 cells at pH 8.0.

Results: Osimertinib reduced iPSC or AC16 viability by 35% compared to cells treated with DMSO (P < 0.005) while other EGFR-targeting TKIs did not (P > 0.05). AC16 sensitivity to osimertinib was exacerbated in the presence of cimetidine (P = 0.004) or with diminished expression of either MATE1 or the IGF1R kinase (P < 0.05). Osimertinib disposition was altered 1.4-fold in the presence of MATE1 overexpression (P = 0.004).

Conclusion: We found for the first time that osimertinib reduces cardiomyocyte viability at clinically relevant concentrations. Osimertinib is also a substrate for MATE1 and diminished MATE1 or IGF1R expression increases cardiomyocyte toxicity.