ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.

Autor:	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., Hill KD; Pharmacokinetics Laboratory, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Anderson LW; Pharmacokinetics Laboratory, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, 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; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: frank.szulzewsky@hsc.utah.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Oct 22; Vol. 43 (10), pp. 114829. Date of Electronic Publication: 2024 Oct 03.
DOI:	10.1016/j.celrep.2024.114829
Abstrakt:	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 develop a series of genetically engineered mouse models of treatment-naive and -experienced NTRK1/2/3 fusion-driven gliomas. All tested NTRK fusions are oncogenic in vivo. The NTRK variant, N-terminal fusion partners, and resistance-associated point mutations all influence tumor histology and aggressiveness. Additional tumor suppressor losses greatly enhance tumor aggressiveness. Treatment with TRK kinase inhibitors significantly extends the survival of NTRK fusion-driven glioma mice, but fails to fully eradicate tumors, leading to recurrence upon treatment discontinuation. 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 to study therapy resistance of NTRK fusion tumors. Competing Interests: Declaration of interests The authors declare that they have no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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