Four decades of the RET gene: From discovery to tumor-agnostic therapy

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• The Rearranged during Transfection (RET) gene encodes a receptor tyrosine kinase involved in development.
• RET signaling requires glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and GFRα coreceptors.
• RET alterations are linked to various cancers and developmental disorders, including thyroid and lung cancers.

Purpose of the Study:

• To review the physiological and disease-related roles of the RET gene.
• To highlight the clinical efficacy of selective RET kinase inhibitors.
• To discuss the emerging paradigm of tumor-agnostic therapies targeting RET.

Main Methods:

• Literature review of studies on RET gene function, alterations, and therapeutic targeting.
• Analysis of clinical trial data for selective RET inhibitors in various cancers.
• Synthesis of information on RET's role in normal development and disease pathogenesis.

Main Results:

• RET gene rearrangements and mutations are prevalent in specific cancers like papillary thyroid carcinoma and non-small cell lung carcinoma.
• RET alterations are also associated with multiple endocrine neoplasia and Hirschsprung's disease.
• Selective RET kinase inhibitors demonstrate significant clinical efficacy in advanced RET-altered cancers.

Conclusions:

• Targeting RET with selective inhibitors represents a significant advancement in cancer therapy.
• The efficacy of RET inhibitors across multiple tumor types supports a tumor-agnostic therapeutic approach.
• Further research into RET signaling pathways may uncover new therapeutic strategies.