Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy

TLDR

Tyrosine kinases drive cancer cell proliferation, apoptosis, and angiogenesis, making them key therapeutic targets, yet emerging evidence shows that tumors frequently develop acquired resistance to monoclonal antibodies and small‑molecule inhibitors. This review surveys the latest molecular mechanisms underlying acquired resistance to tyrosine‑kinase inhibitors to inform the development of strategies that prevent or overcome such resistance. The mechanisms are identified through in‑vitro models and analyses of patient samples.

Abstract

Abstract In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients.