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

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 accumulat...

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Published in:	Cell reports (Cambridge) Vol. 43; no. 10; p. 114829
Main Authors:	Schmid, Sebastian, Russell, Zachary R., Yamashita, Alex Shimura, West, Madeline E., Parrish, Abigail G., Walker, Julia, Rudoy, Dmytro, Yan, James Z., Quist, David C., Gessesse, Betemariyam N., Alvinez, Neriah, Hill, Kimberly D., Anderson, Larry W., Cimino, Patrick J., Kumasaka, Debra K., Parchment, Ralph E., Holland, Eric C., Szulzewsky, Frank
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 22-10-2024 Elsevier
Subjects:	CP: Cancer Entrectinib gene fusion Larotrectinib mouse models NTRK pediatric glioma Repotrectinib RTK targeted therapy Trametinib mouse models targeted therapy Larotrectinib Repotrectinib CP: Cancer gene fusion RTK Entrectinib NTRK pediatric glioma Trametinib
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Summary:	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. [Display omitted] •Both N-terminal fusion partner and NTRK variant influence tumor aggressiveness and biology•Tyrosine kinase inhibition prolongs survival, but persister cells lead to recurrence•Resistance-associated point mutations influence response to therapy in vivo•MEK inhibition leads to a significant growth inhibition in vivo Here, Schmid et al. develop a series of NTRK fusion-driven GEMMs of pediatric-type glioma. Treatment with TRK kinase inhibitors significantly prolongs survival, but tumors eventually recur due to treatment-resistant persister cells. These tumors upregulate the Ras-Raf-MEK-ERK and PI3K-AKT-mTOR pathways, and MEK inhibition by itself leads to a significant growth inhibition.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, S.S., Z.R.R., D.K.K., R.E.P., E.C.H., and F.S.; performed experiments, S.S., Z.R.R., A.S.Y., M.E.W., J.W., D.R., J.Z.Y., K.D.H., L.W.A., and F.S.; data analysis, S.S., Z.R.R., A.S.Y., A.G.P., D.C.Q., B.N.G., N.A., K.D.H., L.W.A., P.J.C., and F.S.; original manuscript writing, S.S., P.J.C., E.C.H., and F.S.; review and editing, E.C.H. and F.S.; funding acquisition, E.C.H.; supervision, R.E.P., E.C.H., and F.S. All authors read, reviewed, and approved the manuscript.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2024.114829