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 tumordependent 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.T he seminal finding of BCR-ABL tyrosine kinase activity (1) and the subsequent development of the small-molecule inhibitor imatinib (2) have pioneered an era of therapies targeted toward mutated tyrosine kinases in cancer. Advancements in genomic sequencing and in our understanding of tumor signaling pathways have revealed several mutated and nonmutated pathway-activated tyrosine kinases. In this minireview, we will describe the different mechanisms of tyrosine kinase activation and how therapies tailored to these kinases have transformed disease outcomes. In particular, we will highlight two main examples of tyrosine kinases investigated in our lab, BCR-ABL and Bruton's tyrosine kinase (BTK). We will also examine a shifting paradigm in which nonmutated tyrosine kinases are being considered primary targets for tyrosine kinase inhibitor (TKI) therapy in cancer. Finally, we will discuss how phosphoproteomic approaches can identify activation of nonmutated kinase pathways and the challenges that we face by clinically targeting activated wild-type tyrosine kinases. TYROSINE KINASE SIGNALINGSince the discovery of v-SRC and v-ABL tyrosine phosphorylation 35 years ago (3, 4), considerable progress has been made in understanding how tyrosine phosphorylation contributes to normal cellular homeostasis and disease. Tyrosine phosphorylation is regulated by a family of enzymes known as tyrosine kinases. Tyrosine kinases are crucial mediators of normal cellular signal transduction functions, including cell proliferation, survival, migration, and apoptosis. Humans expr...

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