KIT proto-oncogene receptor tyrosine kinase and Ret proto-oncogene (KIT/RET)

The term "c-KIT, RET and additional kinases" refers to a cluster of receptor tyrosine kinases (RTKs) that are frequently co-targeted by broad-spectrum multi-kinase inhibitors (MKIs). KIT (also known as CD117) is a type III RTK essential for hematopoiesis and the function of mast cells, with its oncogenic activation being a hallmark of gastrointestinal stromal tumors (GIST) and systemic mastocytosis. RET is a transmembrane receptor required for the development of the nervous and genitourinary systems; its dysregulation via mutations or chromosomal rearrangements is a primary driver in medullary thyroid cancer and a subset of non-small cell lung cancers. The "additional kinases" typically inhibited alongside KIT and RET in clinical practice include the Vascular Endothelial Growth Factor Receptors (VEGFR) and Platelet-Derived Growth Factor Receptors (PDGFR), which play critical roles in tumor angiogenesis. Therapeutic agents such as sunitinib, regorafenib, and cabozantinib target this collective group by binding to the intracellular kinase domains, thereby suppressing signaling cascades like the PI3K/AKT and MAPK/ERK pathways. While effective across multiple tumor types, these inhibitors are often associated with a distinct profile of adverse effects, such as hypertension and hand-foot skin reaction, resulting from the simultaneous inhibition of multiple physiological pathways.

Other names

c-KITCD117SCFRMast/stem cell growth factor receptor KitPBTRETCDHF12CDHR16HSCR1MEN2AMEN2BMTC1PTCRET51

Inhibition of the intracellular tyrosine kinase domain by competing with ATP for binding, which prevents autophosphorylation and blocks downstream signaling pathways such as PI3K/AKT, MAPK/ERK, and STAT, ultimately inhibiting cell proliferation and survival.