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
Affiliations
Jinyang Cai
Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Sheeba Jacob
Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Richard Kurupi
Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Krista M. Dalton
Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Colin Coon
Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Patricia Greninger
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Regina K. Egan
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Giovanna T. Stein
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Ellen Murchie
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Joseph McClanaghan
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
Yuta Adachi
Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan
Kentaro Hirade
Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan
Mikhail Dozmorov
Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA
John Glod
National Cancer Institute, Pediatric Branch, Oncology, Bethesda, MD, USA
Sosipatros A. Boikos
Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
Hiromichi Ebi
Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan
Huaixiang Hao
Novartis Institute for Biological Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA
Giordano Caponigro
Novartis Institute for Biological Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA
Cyril H. Benes
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA; Corresponding author
Anthony C. Faber
Philips Institute for Oral Health Research, School of Dentistry, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA; Corresponding author
Summary: 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.
