RET Signaling Pathway in Human Cancer: Oncogenic Mechanisms, Selective Inhibitors, and Emerging Resistance Strategies

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The proto-oncogene Rearranged During Transfection (RET) encodes a receptor tyrosine kinase vital for development.
• Aberrant RET signaling through mutations and fusions drives oncogenesis in various cancers, including thyroid and lung cancers.
• Constitutive activation of downstream pathways like RAS-MAPK, PI3K-AKT, and JAK-STAT is implicated in RET-driven tumorigenesis.

Purpose of the Study:

• To review the role of RET alterations in oncogenesis.
• To evaluate the efficacy and limitations of current RET inhibitors.
• To discuss emerging strategies for overcoming therapeutic resistance in RET-altered malignancies.

Main Methods:

• Literature review of studies on RET proto-oncogene, its alterations, and targeted therapies.
• Analysis of clinical trial data for early and selective RET inhibitors.
• Examination of mechanisms of resistance to RET-targeted therapies.

Main Results:

• Early multi-kinase inhibitors (e.g., vandetanib, cabozantinib) had limited efficacy and significant toxicity.
• Selective RET inhibitors (e.g., selpercatinib, pralsetinib) offer improved response rates and tolerability.
• Therapeutic resistance arises from secondary RET mutations and bypass signaling pathways (e.g., MET, EGFR).

Conclusions:

• Selective RET inhibitors represent a significant advancement in treating RET-altered cancers.
• Overcoming resistance mechanisms is essential for improving long-term patient outcomes.
• Next-generation inhibitors and combination therapies are key to advancing precision oncology for these malignancies.