Faculty, Staff and Student Publications
Adaptive Darwinian Off-Target Resistance Mechanisms to Selective RET Inhibition in RET Driven Cancer
Publication Date
3-4-2024
Journal
NPJ Precision Oncology
DOI
10.1038/s41698-024-00563-4
PMID
38438731
PMCID
PMC10912412
PubMedCentral® Posted Date
March 2024
PubMedCentral® Full Text Version
Post-print
Abstract
Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.
Published Open-Access
yes
Recommended Citation
Subbiah, Vivek; Gouda, Mohamed A; Iorgulescu, J Bryan; et al., "Adaptive Darwinian Off-Target Resistance Mechanisms to Selective RET Inhibition in RET Driven Cancer" (2024). Faculty, Staff and Student Publications. 1634.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/1634
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