Activation of TRKA receptor elicits mastocytosis in mice and is involved in the development of resistance to KIT-targeted therapy

Oncotarget
Min YangZhixiong Li

Abstract

The neurotrophins (NTs) play a key role in neuronal survival and maintenance. The TRK (tropomyosin-related kinase) tyrosine kinase receptors (TRKA, TRKB, TRKC) are high affinity receptors for NTs. There is increasing data demonstrating an important role of the TRK family in cancer initiation and progression. NTs have been known for many years to promote chemotaxis, maturation, and survival of mast cells. However, the role of NT signaling in the pathogenesis of mastocytosis is not well understood. In this study, we demonstrate that activation of TRKA by its ligand nerve growth factor (NGF) is potent to trigger a disease in mice with striking similarities to human systemic mastocytosis (SM). Moreover, activation of TRKA by NGF strongly rescues KIT inhibition-induced cell death of mast cell lines and primary mast cells from patients with SM, and this rescue effect can be efficiently blocked by entrectinib (a new pan TRK specific inhibitor). HMC-1 mast cell leukemia cells that are resistant to KIT inhibition induced by TRKA activation show reactivation of MAPK/ERK (extracellular signal-regulated kinase) and strong upregulation of early growth response 3 (EGR3), suggesting an important role of MAPK-EGR3 axis in the development of re...Continue Reading

References

Oct 28, 1997·European Journal of Immunology·G NilssonD D Metcalfe
Sep 10, 1998·Nature Genetics·W G Tourtellotte, J Milbrandt
Apr 4, 2002·In Vitro Cellular & Developmental Biology. Animal·Cord C Uphoff, Hans G Drexler
Apr 20, 2002·Science·Zhixiong LiChristopher Baum
Mar 23, 2004·Biochemical and Biophysical Research Communications·Rocío GarcíaNancy Pavón
Jul 12, 2005·Proceedings of the National Academy of Sciences of the United States of America·Ching-Cheng ChenStephen J Galli
Dec 15, 2005·The Journal of Experimental Medicine·Jacques P ZappullaRoland S Liblau
Oct 25, 2006·Molecular and Cellular Biology·Zhifu XiangMichael H Tomasson
Nov 2, 2006·Proceedings of the National Academy of Sciences of the United States of America·Yiguo HuShaoguang Li
Mar 14, 2007·Molecular and Cellular Neurosciences·Lin LiWarren G Tourtellotte
Jun 21, 2008·Blood·Sebastian NewrzelaDorothee von Laer
Jun 12, 2012·Nature Medicine·Alex KentsisA Thomas Look
Mar 15, 2013·Biochemical and Biophysical Research Communications·Sarah Q ToColin D Clyne
Jul 6, 2014·British Journal of Haematology·Tugce B BalciJason N Berman
Feb 18, 2015·American Journal of Hematology·Animesh Pardanani
May 24, 2015·Journal of Cancer Research and Clinical Oncology·Andreas HochhausHagop M Kantarjian
Jul 15, 2015·The New England Journal of Medicine·Theoharis C TheoharidesCem Akin
Nov 14, 2015·Journal of the National Cancer Institute·Andrea Sartore-BianchiSalvatore Siena
Feb 20, 2016·Annals of Hematology·Kezhi HuangZhixiong Li
Jun 30, 2016·The New England Journal of Medicine·Jason GotlibAndreas Reiter

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Citations

Sep 26, 2019·Leukemia·Sunil K JoshiCristina E Tognon
Feb 23, 2020·Clinical Reviews in Allergy & Immunology·Daniel Elieh Ali KomiIan M Adcock
Jun 3, 2021·International Journal of Molecular Sciences·Zhixiong Li
Oct 14, 2021·Acta Dermato-venereologica·Dominika Kwiatkowska, Adam Reich

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Methods Mentioned

BETA
dissection
PCR
xenograft

Clinical Trials Mentioned

NCT02013648

Software Mentioned

Inform
Mantra

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