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Progresses Toward Precision Medicine in RET-altered Solid Tumors
Carmen Belli1, Santosh Anand2,3, Justin F Gainor4
1Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.
Abstract:
RET (rearranged during transfection) gene encodes a receptor tyrosine kinase essential for many physiologic functions, but RET aberrations are involved in many pathologies. While RET loss-of-function mutations are associated with congenital disorders like Hirschsprung disease and CAKUT, RET gain-of-function mutations and rearrangements are critical drivers of tumor growth and proliferation in many different cancers. RET-altered (RET ) tumors have been hitherto targeted with multikinase inhibitors (MKI) having anti-RET activities, but they inhibit other kinase targets more potently and show limited clinical activities. The lack of target specificity and consequently increased side effects, responsible for dose reduction and drug discontinuation, are critical limitations of MKIs in the clinics. New selective RET inhibitors, selpercatinib and pralsetinib, are showing promising activities, improved response rates, and more favorable toxicity profiles in early clinical trials. This review critically discusses the oncogenic activation of RET and its role in different kinds of tumors, clinical features of RET tumors, clinically actionable genetic RET alterations and their diagnosis, and the available data and results of nonselective and selective targeting of RET.
Insights
The rearranged during transfection (RET) gene is crucial for normal functions but its alterations drive cancers. Selective RET inhibitors show promising results, overcoming limitations of older multikinase inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The rearranged during transfection (RET) gene encodes a receptor tyrosine kinase vital for physiological processes.
- RET aberrations, including loss-of-function mutations (Hirschsprung disease, CAKUT) and gain-of-function mutations/rearrangements, are implicated in various pathologies, notably cancer.
- Multikinase inhibitors (MKIs) targeting RET have shown limited efficacy and significant side effects due to lack of specificity.
Purpose of the Study:
- To review the oncogenic activation of RET and its role in tumorigenesis.
- To discuss the clinical features and actionable genetic alterations of RET-altered tumors.
- To evaluate the efficacy and safety of nonselective and selective RET-targeting agents.
Main Methods:
- Literature review of studies on RET gene function, aberrations, and targeted therapies.
- Analysis of clinical trial data for multikinase inhibitors and selective RET inhibitors.
- Discussion of diagnostic approaches for RET alterations.
Main Results:
- RET aberrations are key drivers in various cancers, with distinct clinical presentations.
- Nonselective MKIs targeting RET have shown limited clinical activity and considerable toxicity.
- Selective RET inhibitors, selpercatinib and pralsetinib, demonstrate promising efficacy and improved safety profiles in early trials.
Conclusions:
- Targeting RET is a validated therapeutic strategy in oncology.
- Selective RET inhibitors represent a significant advancement, offering improved outcomes and tolerability for RET-altered tumors.
- Further research and clinical application of selective RET inhibitors are warranted.
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