RET Proto-Oncogene-Not Such an Obvious Starting Point in Cancer Therapy

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• The rearranged during transfection (RET) gene is implicated in various cancers, including thyroid and non-small cell lung cancers.
• Traditional multiple kinase inhibitors (MKIs) have limited efficacy and significant side effects in patients with RET-altered tumors.
• Emerging resistance mutations and alternative signaling pathways can compromise the effectiveness of cancer therapies.

Purpose of the Study:

• To review the role of the RET receptor in normal physiology and cancer.
• To outline the molecular alterations of the RET gene in different malignancies.
• To evaluate the efficacy of current and novel anticancer therapies targeting RET alterations.

Main Methods:

• Literature review of studies on RET gene mutations, cancer therapies, and drug resistance.
• Analysis of clinical trial data for RET-specific inhibitors (selpercatinib, pralsetinib) and MKIs.
• Examination of diagnostic methods for detecting RET gene abnormalities.

Main Results:

• RET alterations are key drivers in specific cancers, notably thyroid and lung cancers.
• Novel RET-specific inhibitors (selpercatinib, pralsetinib) demonstrate superior efficacy and safety profiles compared to MKIs.
• Mechanisms of resistance, including secondary RET mutations and pathway reactivation, are critical challenges.

Conclusions:

• RET-specific inhibitors represent a significant advancement in treating RET-driven cancers.
• Understanding and overcoming resistance mechanisms are crucial for optimizing patient outcomes.
• A comprehensive approach integrating diagnostics and targeted therapies is essential for managing RET-altered malignancies.