Advances in studies of tyrosine kinase inhibitors and their acquired resistance

Abstract

Protein tyrosine kinase (PTK) is one of the major signaling enzymes in the process of cell signal transduction, which catalyzes the transfer of ATP-γ-phosphate to the tyrosine residues of the substrate protein, making it phosphorylation, regulating cell growth, differentiation, death and a series of physiological and biochemical processes. Abnormal expression of PTK usually leads to cell proliferation disorders, and is closely related to tumor invasion, metastasis and tumor angiogenesis. At present, a variety of PTKs have been used as targets in the screening of anti-tumor drugs. Tyrosine kinase inhibitors (TKIs) compete with ATP for the ATP binding site of PTK and reduce tyrosine kinase phosphorylation, thereby inhibiting cancer cell proliferation. TKI has made great progress in the treatment of cancer, but the attendant acquired acquired resistance is still inevitable, restricting the treatment of cancer. In this paper, we summarize the role of PTK in cancer, TKI treatment of tumor pathways and TKI acquired resistance mechanisms, which provide some reference for further research on TKI treatment of tumors.

Keywords: Acquired resistance; Cancer; Protein tyrosine kinase; Tyrosine kinase inhibitors.

Fig. 1

Cell signaling pathways induced by RTK. RTK can bind to ligands and phosphorylate tyrosine residues of target proteins and transmit information through PI3K/AKT/mTOR; RAS/RAF/MEK/ERK; PLCγ/PKC and other signaling pathways to activate a series of biochemical reactions; or different information combined to cause a comprehensive cellular response, including cell proliferation, cell migration and tumor formation

Fig. 2

Cell signaling pathways induced by Src kinases. Src kinases regulate a broad spectrum of cellular events such as cell adhesion, proliferation and mobility. These include the STAT3 pathway that regulates the expression of c-Myc and Cyclin D1; the RAS/RAF/MEK/ERK pathway; and the PI3K/AKT/mTOR pathway

Fig. 3

Cell signaling pathways induced by Abl kinases. Phosporylated Abl activates oncogenic signaling pathways by activation of ERK5; Rac/Jnk, and STAT 1/3 pathways. These cascades are required for cancer cell growth and transformation