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Updated: Aug 18, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting RET alterations in cancer: Recent progress and future directions
Arafat Shabbir1, Arsenije Kojadinovic2, Tabinda Shafiq3
1Department of Medicine, Yale New Haven Hospital, USA.
Abstract:
Genomic alterations in the receptor tyrosine kinase RET represent actionable driver events in several cancer types. Activation of the kinase domain by point mutations represents a pathognomonic event in medullary thyroid cancer, while RET fusions are critical driver events in a sizable subset of differentiated thyroid cancer and a smaller percentage of lung cancer. Early trials with multi-kinase inhibitors yielded modest improvement in outcomes for RET-driven cancers. In recent years, highly selective RET inhibitors entered clinical trials and demonstrated remarkable response rates, resulting in accelerated approval for selpercatinib and pralsetinib in 2020. An important mechanism of eventual resistance to RET inhibitors is the emergence of secondary drug resistance mutations, particularly in the solvent front, and several promising compounds are in development to overcome these mutations. Mechanisms of acquired resistance that bypass RET signaling altogether have also been discovered, suggesting that combinatorial drug strategies may be necessary for some patients.
Insights
Targeted therapies, including highly selective RET inhibitors, show promise for RET-driven cancers like thyroid and lung cancer. Research is ongoing to overcome resistance mechanisms for improved patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genomic alterations in the receptor tyrosine kinase RET are key drivers in various cancers, including medullary thyroid cancer (MTC), differentiated thyroid cancer (DTC), and lung cancer.
- While multi-kinase inhibitors offered limited benefits, recent advancements include highly selective RET inhibitors, leading to accelerated approvals for selpercatinib and pralsetinib in 2020.
Purpose of the Study:
- To review the role of RET alterations in cancer.
- To discuss the clinical efficacy of selective RET inhibitors.
- To explore emerging mechanisms of drug resistance and potential therapeutic strategies.
Main Methods:
- Literature review of studies on RET alterations and targeted therapies.
- Analysis of clinical trial data for selective RET inhibitors.
- Examination of research on acquired resistance mechanisms to RET inhibitors.
Main Results:
- Selective RET inhibitors demonstrate significant response rates in RET-driven cancers.
- Secondary mutations in the kinase domain are a primary cause of drug resistance.
- Alternative resistance pathways bypassing RET signaling have been identified.
Conclusions:
- Selective RET inhibitors represent a major advancement in treating RET-driven malignancies.
- Understanding and overcoming resistance mechanisms, including secondary mutations and bypass pathways, is crucial for durable responses.
- Combinatorial drug strategies may be necessary to address complex resistance in some patients.
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