Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers
Jacob J Adashek1,2, Aakash P Desai3, Alexander Y Andreev-Drakhlin4
1Department of Internal Medicine, University of South Florida, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Abstract:
Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.
Insights
Activating RET alterations drive cancer, and new targeted therapies like selpercatinib offer improved treatment. Understanding RET fusions and co-alterations is key for future combination therapies and overcoming resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations and fusions in the rearranged during transfection (RET) receptor tyrosine kinase are oncogenic drivers.
- RET signaling plays a significant role in various cancers, exhibiting phenotypic diversity.
- Emerging data suggest limited responsiveness to immunotherapy in RET-altered cancers.
Purpose of the Study:
- To review registrational data for selective RET inhibitors (selpercatinib, pralsetinib).
- To explore RET alterations and co-alterations across adult malignancies.
- To discuss the implications for future targeted and combination therapies for RET-driven cancers.
Main Methods:
- Review of registrational trial data for selective RET inhibitors.
- Comprehensive analysis of pan-cancer adult RET alterations and co-alterations.
- Exploration of emerging resistance mechanisms.
Main Results:
- Selective RET inhibitors have altered therapeutic management of RET-aberrant tumors.
- RET alterations occur in multiple cancers with significant phenotypic diversity.
- Oncogenic RET fusions can mediate resistance to other targeted therapies like EGFR and KRAS inhibitors.
Conclusions:
- Understanding RET alterations and co-alterations is crucial for developing customized combination therapies.
- Acquired resistance mechanisms, both on-target and off-target, require further investigation.
- Future therapeutic strategies will likely involve tailored approaches beyond selective RET inhibition.
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