RET – ILLUSTRATED MEDICAL COURSES

1. RET Overview

Gene: RET (Rearranged during Transfection)
Protein: RET receptor tyrosine kinase
Chromosome: 10q11.2
Normal Function:
- Transmembrane receptor for glial cell line-derived neurotrophic factor (GDNF) family ligands
- Regulates cell proliferation, differentiation, migration, and survival
- Plays a role in development of kidneys and neural crest–derived tissues

Types of RET alterations:
1. Point mutations (activating mutations):
  - Seen in medullary thyroid carcinoma (MTC) and MEN2 syndromes
  - Examples: M918T, V804M
2. Gene fusions (rearrangements):
  - Seen in non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC)
  - Common fusion partners: KIF5B-RET, CCDC6-RET
Effect: Constitutive RET kinase activation → uncontrolled MAPK, PI3K/AKT, and JAK/STAT signaling → tumor growth

Alteration Type	Tumor Type	Notes
Activating mutations	Medullary thyroid carcinoma (MTC)	Sporadic or hereditary (MEN2A/B)
Fusions	NSCLC	1–2% of lung adenocarcinomas
Fusions	Papillary thyroid carcinoma (PTC)	Often radiation-associated
Rare	Other solid tumors	Occasionally in pancreatic or colorectal cancers

RET inhibitors:
- Selective RET TKIs (first-line targeted therapy for RET-altered cancers):
  - Selpercatinib (LOXO-292) – NSCLC, MTC, PTC
  - Pralsetinib (BLU-667) – NSCLC, MTC, PTC
- Multi-kinase inhibitors (less selective, higher toxicity):
  - Cabozantinib, Vandetanib – older options for RET-mutant MTC
Mechanism: Inhibit RET kinase → block downstream MAPK/PI3K/STAT signaling → tumor growth suppression

Testing:
- DNA or RNA sequencing for RET mutations/fusions in thyroid cancer, NSCLC
- Important for selecting targeted therapy
Adverse Effects of selective RET inhibitors:
- Hypertension, liver enzyme elevation, fatigue, QT prolongation, GI effects
Resistance:
- Solvent front mutations (G810R/S) → resistance to first-generation RET inhibitors
- Next-generation RET inhibitors in development to overcome resistance

Summary