KIT (CD117)

KIT is a transmembrane receptor tyrosine kinase encoded by the KIT proto-oncogene. It is also known as CD117.

Normal Physiology

• Ligand: Stem cell factor (SCF)
• Activation → receptor dimerization → autophosphorylation
• Downstream signaling pathways:
  • PI3K/AKT
  • RAS/MAPK
  • JAK/STAT
• Regulates:
  • Hematopoiesis
  • Melanocyte development
  • Germ cell survival
  • Interstitial cells of Cajal (GI pacemaker cells)

Oncologic Relevance

Gain-of-function KIT mutations lead to constitutive signaling independent of SCF.

Most commonly seen in:

• Gastrointestinal stromal tumor
• Systemic mastocytosis
• Some melanomas
• Core-binding factor AML (subset)

Therapeutic Implications

KIT-mutant tumors are targetable with TKIs:

• Imatinib – first-line in KIT-mutant GIST
• Sunitinib – second-line
• Regorafenib – later-line
• Avapritinib – active in PDGFRA D842V and select KIT mutations

Mutation exon location (e.g., exon 11 vs exon 9) influences:

• Dose selection
• Resistance patterns
• TKI sequencing

High-Yield Pharmacist Pearls

• Exon 11 mutations → best response to imatinib
• Exon 9 mutations → may require higher imatinib dose
• Secondary mutations drive acquired resistance
• Not all CD117-positive tumors are KIT-mutated (IHC ≠ mutation)