Integrated Mathematical Analysis of Anticancer and Cardiac Hypofunction Effects of HER2 Inhibitors

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K15782
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43060:System genome science-related
• Research Institution: Toho University
• Principal Investigator: Magi Shigeyuki 東邦大学, 医学部, 助教 (90708546)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HER2シグナル / がん細胞 / 心筋細胞

Outline of Final Research Achievements

We attempted to identify the molecular responses contributing to anti-HER2 therapeutic antibody trastuzumab (TRZ)-induced cardiac dysfunction by constructing a mathematical model that can reproduce HER2 signaling in HER2-positive breast cancer cells and cardiomyocytes.
First, we evaluated the effects of TRZ and the HER2-activating ligand NRG1 on phosphorylation signaling downstream of HER2, cell viability, and cardiomyocyte beating in breast cancer cells and cardiomyocytes.
We then constructed a mathematical model based on experimental data on HER2 signaling and mRNA expression levels in cardiomyocytes. Optimization of the mathematical model for cardiomyocytes resulted in reaction parameters that were different from the model derived from breast cancer cells.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた乳がん細胞と心筋細胞におけるHER2シグナル伝達の違いは、乳がん治療におけるトラスツズマブの使用に関連する潜在的な心筋毒性を理解し、病態に適した治療戦略を導き出すための基礎情報となる。また、心筋細胞のHER2シグナルを再現できる数理モデルは、トラスツズマブが誘導する心機能低下を軽減する薬物の開発に寄与する可能性がある。