Clinical targeting of mutated and wild-type protein tyrosine kinases in cancer

Abstract

Clinical therapies for cancer have evolved from toxic, nontargeted agents to manageable, highly targeted therapies. Protein tyrosine kinases are a family of signaling molecules implicated in nearly every cancer type and are the foundation for the development of modern targeted agents. Recent genomic analyses have identified activating mutations, translocations, and amplifications of tyrosine kinases. Selective targeting of these genetically altered tyrosine kinases has resulted in significant clinical advances, including increased patient survival. This indicates that altered protein tyrosine kinases are the main drivers of many different cancers. However, lost during analyses of genetic lesions are the contributions of activated, wild-type kinases on tumor-dependent pathways. New approaches in phosphoproteomic technologies have identified several wild-type tyrosine kinase activation states, suggesting that non-genetically altered kinases can be essential "nodes" for signal transduction. Here, we summarize the evidence supporting the common mechanisms of protein tyrosine kinase activation in cancer and provide a personal perspective on the kinases BCR-ABL and BTK, as well as nonmutated kinase targets in prostate cancer, through our work. We outline the mechanisms of tyrosine kinase activation in the absence of direct mutation and discuss whether non-genetically altered tyrosine kinases or their associated downstream signaling pathways can be effectively targeted.

FIG 1

Mechanisms of mutated and wild-type tyrosine kinase activation in cancer. Three prototypical mechanisms of genetically altered tyrosine kinase activation as evidenced through genetic alterations. Shown are examples of mutations (A), amplifications (B), or translocations (C) that render a kinase constitutively active and thus contribute to the addiction of tumor cells on pathways driven by the genetically altered kinase. In the absence of genetic alterations (D to F), nonmutated tyrosine kinases can be activated via many different mechanisms and contribute to pathway signaling. In all cases, this pathway addiction leads to increased tumor cell proliferation and survival. In some cases, highly potent therapies that inhibit (red) the altered protein kinase have resulted in robust clinical outcomes. RTK, receptor tyrosine kinase; Chr, chromosome; Ph¹, Philadelphia chromosome; BCR, breakpoint cluster region; Ag, antigen; BTK, Bruton's tyrosine kinase; PTP1B, protein tyrosine phosphatase 1B.