Progress and challenges in RET-targeted cancer therapy.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The rearranged during transfection (RET) gene encodes a receptor protein tyrosine kinase implicated in various cancers, notably non-small cell lung cancer (NSCLC) and thyroid cancer.
• Activating mutations and fusions in RET are key oncogenic drivers, leading to the development of targeted therapies.
• While effective, current RET inhibitors like pralsetinib and selpercatinib face challenges with acquired resistance and incomplete responses.

Purpose of the Study:

• To review the mechanisms of resistance to current RET inhibitors.
• To discuss the development of next-generation RET inhibitors.
• To highlight the need for novel therapeutic strategies to overcome treatment resistance and eliminate residual disease.

Main Methods:

• Literature review of studies on RET inhibitors, resistance mechanisms, and emerging therapies.
• Analysis of clinical trial data and preclinical research findings.
• Identification of key resistance mutations, such as RET G810.

Main Results:

• Pralsetinib and selpercatinib achieve high response rates but rarely complete responses, with residual tumors developing resistance.
• RET G810 mutations are a primary on-target resistance mechanism against current RET TKIs.
• Next-generation RET inhibitors are in clinical trials, but further resistance mutations are anticipated.

Conclusions:

• Understanding the multifaceted mechanisms of resistance is crucial for developing effective treatments.
• Identifying vulnerabilities in persistent tumor cells is key to devising combination therapies.
• The ultimate goal is to eradicate residual tumors and improve long-term outcomes for patients with RET-altered cancers.