Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7

Qing Liu; Suyao Li; Yuran Qiu; Jiayu Zhang; Francisco J Rios; Zhiguo Zou; Rhian M Touyz

doi:10.3389/fcvm.2023.1002438

Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7

Front Cardiovasc Med. 2023 Feb 3:10:1002438. doi: 10.3389/fcvm.2023.1002438. eCollection 2023.

Authors

Qing Liu^{1

2}, Suyao Li¹, Yuran Qiu³, Jiayu Zhang¹, Francisco J Rios⁴, Zhiguo Zou⁵, Rhian M Touyz⁴

Affiliations

¹ Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
³ State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada.
⁵ Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity. Mechanisms underlying TKI-induced cardiovascular toxicity remain unclear. The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme consisting of a membrane-based ion channel and intracellular α-kinase. TRPM7 is a cation channel that regulates transmembrane Mg²⁺ and Ca²⁺ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias. Of importance, we and others demonstrated significant cross-talk between TRPM7, RTKs, and TK signaling in different cell types including vascular smooth muscle cells (VSMCs), which might be a link between TKIs and their cardiovascular effects. In this review, we summarize the implications of RTK inhibitors (RTKIs) and TKIs in cardiovascular toxicities during anti-cancer treatment, with a focus on the potential role of TRPM7/Mg²⁺ as a mediator of RTKI/TKI-induced cardiovascular toxicity. We also describe the important role of TRPM7 in cancer development and cardiovascular diseases, and the interaction between TRPM7 and RTKs, providing insights for possible mechanisms underlying cardiovascular disease in cancer patients treated with RTKI/TKIs.

Keywords: TRPM7; calcium; cancer; cardiovascular toxicities; cation channel; magnesium; receptor tyrosine kinase; tyrosine kinase inhibitors.

Publication types

Review

Grants and funding

RT was supported by grants from the Leducq Foundation, Dr. Phil Gold Chair, McGill University and European Commission, and Canada Research Chair Program of the Canadian Institutes of Health Research. ZZ was sponsored by Shanghai Pujiang Program (21PJD039).