High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition.

Autor:	Cai J; Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA., Jacob S; Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA., Kurupi R; Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA., Dalton KM; Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA., Coon C; Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA., Greninger P; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA., Egan RK; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA., Stein GT; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA., Murchie E; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA., McClanaghan J; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA., Adachi Y; Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan., Hirade K; Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan., Dozmorov M; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA., Glod J; National Cancer Institute, Pediatric Branch, Oncology, Bethesda, MD, USA., Boikos SA; Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA., Ebi H; Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan., Hao H; Novartis Institute for Biological Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA., Caponigro G; Novartis Institute for Biological Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA., Benes CH; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Electronic address: cyrilbenes@gmail.com., Faber AC; Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: acfaber@vcu.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Jul 26; Vol. 40 (4), pp. 111095.
DOI:	10.1016/j.celrep.2022.111095
Abstrakt:	Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB. Competing Interests: Declaration of interests C.H.B. is an employee of Novartis and previously received funding from Novartis. A.C.F. is a current scientific advisor for Treeline Biosciences and was a past scientific advisor for AbbVie. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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