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Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer
- Source :
- npj Precision Oncology, Vol 8, Iss 1, Pp 1-9 (2024)
- Publication Year :
- 2024
- Publisher :
- Nature Portfolio, 2024.
-
Abstract
- 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.
- Subjects :
- Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Subjects
Details
- Language :
- English
- ISSN :
- 2397768X and 53204816
- Volume :
- 8
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- npj Precision Oncology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.2cb1c36a9a5542459cc53204816c9e28
- Document Type :
- article
- Full Text :
- https://doi.org/10.1038/s41698-024-00563-4