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

Jinyang Cai; Sheeba Jacob; Richard Kurupi; Krista M Dalton; Colin Coon; Patricia Greninger; Regina K Egan; Giovanna T Stein; Ellen Murchie; Joseph McClanaghan; Yuta Adachi; Kentaro Hirade; Mikhail Dozmorov; John Glod; Sosipatros A Boikos; Hiromichi Ebi; Huaixiang Hao; Giordano Caponigro; Cyril H Benes; Anthony C Faber

doi:10.1016/j.celrep.2022.111095

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

Cell Rep. 2022 Jul 26;40(4):111095. doi: 10.1016/j.celrep.2022.111095.

Authors

Jinyang Cai¹, Sheeba Jacob¹, Richard Kurupi¹, Krista M Dalton¹, Colin Coon¹, Patricia Greninger², Regina K Egan², Giovanna T Stein², Ellen Murchie², Joseph McClanaghan², Yuta Adachi³, Kentaro Hirade³, Mikhail Dozmorov⁴, John Glod⁵, Sosipatros A Boikos⁶, Hiromichi Ebi³, Huaixiang Hao⁷, Giordano Caponigro⁷, Cyril H Benes⁸, Anthony C Faber⁹

Affiliations

¹ Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
² Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
³ Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan.
⁴ Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁵ National Cancer Institute, Pediatric Branch, Oncology, Bethesda, MD, USA.
⁶ Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁷ Novartis Institute for Biological Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
⁸ Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. Electronic address: cyrilbenes@gmail.com.
⁹ 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.

Abstract

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.

Keywords: CP: Cancer; MEK inhibitor; SHP099; high-risk neuroblastoma; neurofibromin, NF1.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line, Tumor
Mice
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Neoplasm Recurrence, Local
Neuroblastoma* / drug therapy
Neuroblastoma* / genetics
Neuroblastoma* / pathology
Neurofibromin 1* / genetics
Neurofibromin 1* / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*

Substances

Neurofibromin 1
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Protein Tyrosine Phosphatase, Non-Receptor Type 11

Abstract

Publication types

MeSH terms

Substances

Grants and funding