ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models
Sebastian Schmid,
Zachary R. Russell,
Alex Shimura Yamashita,
Madeline E. West,
Abigail G. Parrish,
Julia Walker,
Dmytro Rudoy,
James Z. Yan,
David C. Quist,
Betemariyam N. Gessesse,
Neriah Alvinez,
Kimberly D. Hill,
Larry W. Anderson,
Patrick J. Cimino,
Debra K. Kumasaka,
Ralph E. Parchment,
Eric C. Holland,
Frank Szulzewsky
Affiliations
Sebastian Schmid
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Zachary R. Russell
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Alex Shimura Yamashita
Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA
Madeline E. West
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Abigail G. Parrish
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Julia Walker
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Dmytro Rudoy
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
James Z. Yan
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
David C. Quist
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Betemariyam N. Gessesse
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Neriah Alvinez
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Kimberly D. Hill
Pharmacokinetics Laboratory, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
Larry W. Anderson
Pharmacokinetics Laboratory, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
Patrick J. Cimino
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Debra K. Kumasaka
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Ralph E. Parchment
Clinical Pharmacodynamic Biomarkers Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21701, USA
Eric C. Holland
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Seattle Translational Tumor Research Center, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
Frank Szulzewsky
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; Corresponding author
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.
