Aims: Treatment of HER2 positive (HER2+) breast cancer has significantly improved since the development of trastuzumab. However, approximately 30 % of patients develop trastuzumab-induced cardiotoxicity (TIC) manifested as a decrease in left ventricular ejection fraction (LVEF), with nearly 5 % of cases progressing to congestive heart failure. While TIC is generally reversible upon treatment discontinuation, the underlying mechanisms of this adverse reaction remain incompletely understood. Emerging evidence suggests that genetic factors may contribute to individual susceptibility. The variant rs1136201 in the ERBB2 gene, also known as HER2 Ile655Val or I655V, has been studied for its association with TIC, yet its role remains controversial. This study investigates the implication of the rs1136201 variant in cardiotoxicity in in vitro models of human cardiomyocytes exposed to trastuzumab.
Methods and results: We generated AC16 ventricular cardiomyocyte cell models representing the three genotypes of the rs1136201 variant and performed transcriptomic analysis following trastuzumab exposure. Furthermore, we established a second model consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients carrying the rs1136201 variant and controls and evaluated the impact of this variant on mitochondrial function and contractility after trastuzumab treatment. Transcriptomic analysis revealed alteration of the electron transport chain, ATP synthesis, cellular respiration, and ribosome biogenesis in cells carrying the rs1136201 variant after trastuzumab exposure. hiPSC-CMs showed a reduction in upstroke (p = 0.0107) and downstroke velocities (p = 0.0117) compared to controls.
Conclusion: Our preliminary findings support the potential role of rs1136201 in TIC and underscore the need for further studies.
Keywords: Cardiomyocytes; Cardiotoxicity; Contractility; HER2 Ile655Val; Mitochondria; Trastuzumab.
Copyright © 2025. Published by Elsevier B.V.