Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
NPJ precision oncology - 8(2024), 1 vom: 04. März, Seite 62 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Subbiah, Vivek [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Revised 07.03.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1038/s41698-024-00563-4 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369285913 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Gouda, Mohamed A |e verfasserin |4 aut | |
| 700 | 1 | |a Iorgulescu, J Bryan |e verfasserin |4 aut | |
| 700 | 1 | |a Dadu, Ramona |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Keyur |e verfasserin |4 aut | |
| 700 | 1 | |a Sherman, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Cabanillas, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Mimi |e verfasserin |4 aut | |
| 700 | 1 | |a Castellanos, Luz E |e verfasserin |4 aut | |
| 700 | 1 | |a Amini, Behrang |e verfasserin |4 aut | |
| 700 | 1 | |a Meric-Bernstam, Funda |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Jie |e verfasserin |4 aut | |
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