Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR

Receptor tyrosine kinases (RTKs) are cell-surface proteins that trigger key cellular responses, such as survival, proliferation, differentiation, migration, and cell-cycle control. As increased activity, abundance, and/or cellular distribution of wild-type and mutant forms of RTKs is often associated with tumor establishment, growth, and progression, several drugs directed to clinically relevant RTKs have entered the pharmaceutical market since the beginning of the twenty-first century, representing innovative approaches for cancer treatment. The modulation strategies include small-molecule tyrosine kinase inhibitors (TKIs), targeting the ATP-binding site of the intracellular TK domain, and monoclonal antibodies directed to the extracellular domain, interfering with RTK activation and/or marking RTK-expressing cells for destruction by the immune system. Even though these drugs clearly represented an impressive breakthrough in the therapy of RTK-addicted tumors, resistance development and detection of refractory tumors have given rise to novel therapeutic challenges, pushing the drug discovery process forward. This chapter focuses particularly on the discussion of several case studies on the development of small-molecule tyrosine kinase inhibitors (TKIs) directed to EGFR, VEGFR, and PDGFR, clinically relevant RTKs, and the subset of advances in this field.