Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020)


Abstract
Tyrosine kinases are implicated in tumorigenesis and progression, and have emerged as major targets for drug discovery. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Over the past 20 years, multiple robust and well-tolerated TKIs with single or multiple targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT have been developed, contributing to the realization of precision cancer medicine based on individual patient’s genetic alteration features. TKIs have dramatically improved patients’ survival and quality of life, and shifted treatment paradigm of various solid tumors. In this article, we summarized the developing history of TKIs for treatment of solid tumors, aiming to provide up-to-date evidence for clinical decision-making and insight for future studies.


https://jhoonline.biomedcentral.com/art ... 20-00977-0

Introduction
According to GLOBOCAN 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer deaths occurred in 2018 worldwide [1]. Targeted agents are superior to traditional chemotherapeutic ones in selectivity, efficacy, and safety by acting on specific targets involved in proliferation and differentiation of cancer cells with minimal activity on normal cells.

At least 58 receptor tyrosine kinases (RTKs) and 32 non-receptor tyrosine kinases (NRTKs) have been found so far [2]. RTKs and NRTKs function by catalyzing the transfer of a phosphoryl group from a nucleoside triphosphate donor to the hydroxyl group of tyrosine residues on protein substrates and then triggering the activation of downstream signaling cascades [3]. Abnormal activation of tyrosine kinases due to mutations, translocations, or amplifications is implicated in tumorigenesis, progression, invasion, and metastasis of malignancies. In addition, wild-type tyrosine kinases can also function as critical nodes for pathway activation in cancer. As such, tyrosine kinases have emerged as major targets for drug discovery [4, 5]. A tyrosine kinase inhibitor (TKI) is designed to inhibit the corresponding kinase from playing its role of catalyzing phosphorylation [6]. Since US Food and Drug Administration (FDA) approved imatinib for the treatment of chronic myeloid leukemia in 2001, multiple potent and well-tolerated TKIs—targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT—have been emerging and contributing to the significant progress in cancer treatment. Besides TKIs with one target, some TKIs block a broader range of targets, such as VEGFR-associated multi-targeted TKIs. Noted that some of the multi-targeted TKIs were initially designed to be highly selective, but they turned out to cover other unexpected targets as well [7, 8].

In this article, we summarized the developing history of TKIs for treatment of solid tumors in the past 20 years (2001–2020). And we presented a schematic summary of the approved TKIs for different targets in Fig. 1.