Targeting T-type channels in cancer: what is on and what is off?

Abstract

Over the last 20 years several studies have demonstrated a pivotal role of T‐type calcium channels (TTCCs) in tumor progression. Cytotoxic effects of TTCC pharmacological blockers have been reported in vitro and in preclinical models. However, the roles of TTCCs in cancer physiology are only beginning to be understood. We discuss current evidence for the signaling pathways and cellular processes stemming from TTCC activity, mainly inferred by inverse reasoning from pharmacological block and, only a few, by gene silencing or channel activation. A thorough analysis indicates that drug‐induced cytotoxicity is partially an off‐target effect. Dissection of on/off‐target activity is paramount in order to elucidate TTCC physiological roles, and to deliver efficacious therapies suited to different cancer types and stages.

This work was funded by the Spanish Ministry of Science and Innovation/FEDER “Una manera de hacer Europa” (“Retos” Program, grant RTI2018‐094739‐BI00 to JH and CC) and Fundació La Marató de TV3 (grant 201909 to C.C.). LA held a predoctoral FI AGAUR fellowship and AV was funded from Fundació La Marató de TV3.