ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.
العنوان: | ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models. |
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المؤلفون: | Schmid S; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Russell ZR; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Yamashita AS; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA., West ME; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Parrish AG; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Walker J; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Rudoy D; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Yan JZ; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Quist DC; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Gessesse BN; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Alvinez N; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Cimino PJ; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA., Kumasaka DK; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Parchment RE; Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA., Holland EC; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.; Seattle Translational Tumor Research Center, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Szulzewsky F; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. |
المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 26. Date of Electronic Publication: 2024 Mar 26. |
نوع المنشور: | Preprint |
اللغة: | English |
بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
مستخلص: | Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naïve and -experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion- and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy. |
معلومات مُعتمدة: | R35 CA253119 United States CA NCI NIH HHS; P30 CA015704 United States CA NCI NIH HHS; U54 CA243125 United States CA NCI NIH HHS; S10 OD026919 United States OD NIH HHS; 75N91019D00024 United States CA NCI NIH HHS |
تواريخ الأحداث: | Date Created: 20240401 Latest Revision: 20240408 |
رمز التحديث: | 20240408 |
مُعرف محوري في PubMed: | PMC10979979 |
DOI: | 10.1101/2024.03.13.584849 |
PMID: | 38558981 |
قاعدة البيانات: | MEDLINE |
DOI: | 10.1101/2024.03.13.584849 |
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