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Updated: Jun 30, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Targeting RET alterations in non-small cell lung cancer
1Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Abstract:
Rearranged during transfection (RET) alterations, which lead to aberrant activation of the RET proto-oncogene, have been identified in various cancers. In non-small cell lung cancer (NSCLC), RET mutations often manifest as RET fusion genes and are observed in 1-2 % of patients with NSCLC. In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. While first-generation RET inhibitors have become part of the standard of care for RET-fusion positive NSCLC, a new challenge has emerged: acquired resistance to RET inhibitors. RET resistance is a complex phenomenon that can manifest as either on-target or off-target resistance. Numerous studies have been conducted to identify the mechanisms behind this resistance. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.
Insights
Rearranged during transfection (RET) alterations drive cancer, particularly non-small cell lung cancer (NSCLC). While RET inhibitors offer new treatments, acquired resistance presents a significant challenge requiring further research.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Rearranged during transfection (RET) proto-oncogene alterations activate oncogenic pathways in various cancers.
- RET fusions are found in 1-2% of non-small cell lung cancer (NSCLC) patients, driving tumor growth.
- Selective RET inhibitors (selpercatinib, pralsetinib) revolutionized NSCLC treatment after FDA approval in 2020.
Purpose of the Study:
- To review the biology of RET in NSCLC.
- To analyze clinical outcomes of RET inhibitors in NSCLC.
- To explore challenges and future directions in overcoming RET inhibitor resistance.
Main Methods:
- Literature review of RET biology, testing methods, and clinical trial data.
- Analysis of mechanisms of on-target and off-target RET resistance.
- Synthesis of current and future therapeutic strategies for RET-altered NSCLC.
Main Results:
- First-generation RET inhibitors are standard care for RET-fusion positive NSCLC.
- Acquired resistance to RET inhibitors is a growing clinical challenge.
- Understanding resistance mechanisms is crucial for developing next-generation therapies.
Conclusions:
- RET alterations are key targets in NSCLC, with inhibitors showing significant efficacy.
- Overcoming acquired resistance is paramount for long-term patient benefit.
- Ongoing research and clinical trials are vital for advancing RET-targeted therapy in NSCLC.
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