Journal article
Targeting RET alterations in cancer: Recent progress and future directions
Critical reviews in oncology/hematology, Vol.181, pp.103882-103882
01/2023
DOI: 10.1016/j.critrevonc.2022.103882
PMID: 36481304
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.
•Activating mutations in RET occur frequently in lung and thyroid cancers.•Gene fusions and kinase domain substitutions are reported in RET-driven cancers.•Selective RET inhibitors selpercatinib and pralsetinib induce impressive responses.•RET inhibitors may eventually move into first-line and adjuvant settings.•Secondary kinase domain mutations appear to only partly explain resistance.
Details
- Title: Subtitle
- Targeting RET alterations in cancer: Recent progress and future directions
- Creators
- Arafat Shabbir - Yale New Haven HospitalArsenije Kojadinovic - Icahn School of Medicine at Mount SinaiTabinda Shafiq - Baptist Health FoundationPrabhjot S. Mundi - James J. Peters VA Medical Center
- Resource Type
- Journal article
- Publication Details
- Critical reviews in oncology/hematology, Vol.181, pp.103882-103882
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.critrevonc.2022.103882
- PMID
- 36481304
- ISSN
- 1040-8428
- eISSN
- 1879-0461
- Language
- English
- Date published
- 01/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984694744902771
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