Targeting Receptor Tyrosine Kinases in Cancer

Abstract

Aberrations in the orderly function of the protein families of receptor tyrosine kinases (RTK) rank among the most frequent oncogenic insults in virtually any type of cancer. The present chapter delineates how RTKs are perturbed in human cancers by multiple mechanisms including mutations, deletions, gene amplification, and by genomic rearrangements resulting in fusion genes along with the molecular mechanisms underlying the transforming and tumorigenic potential of these aberrations. Moreover, aberrations in RTKs hardly ever occur alone, but are embedded in coincidental perturbations in the mechanisms that enhance or attenuate RTK signaling. The most frequent oncogenic aberrations of RTKs have been made readily detectable by routine molecular pathology techniques including sequencing, mutation-specific real-time PCR, immunohistochemistry, or in situ hybridization-based techniques. These technological advances enable the individualized therapeutic administration of RTK-targeting agents including monoclonal antibodies, immunotoxins, decoy receptors, tyrosine kinase inhibitors, and other agents. In patients carefully selected by the type of molecular aberration of their tumors, these agents have demonstrated impressive clinical efficacy. Intrinsic and acquired resistance to RTK-targeting agents, however, dampens the clinical efficacy of these targeted agents and the mechanisms underlying resistance to RTK-targeting agents in clinics are also reviewed. Finally, we envisage clinical strategies to delay or overcome resistance to RTK-targeting agents.