Data-Driven Computational Modeling Identifies Determinants of Glioblastoma Response to SHP2 Inhibition

Cancer Res. 2021 Apr 15;81(8):2056-2070. doi: 10.1158/0008-5472.CAN-20-1756. Epub 2021 Feb 11.


Oncogenic protein tyrosine phosphatases have long been viewed as drug targets of interest, and recently developed allosteric inhibitors of SH2 domain-containing phosphatase-2 (SHP2) have entered clinical trials. However, the ability of phosphatases to regulate many targets directly or indirectly and to both promote and antagonize oncogenic signaling may make the efficacy of phosphatase inhibition challenging to predict. Here we explore the consequences of antagonizing SHP2 in glioblastoma, a recalcitrant cancer where SHP2 has been proposed as a useful drug target. Measuring protein phosphorylation and expression in glioblastoma cells across 40 signaling pathway nodes in response to different drugs and for different oxygen tensions revealed that SHP2 antagonism has network-level, context-dependent signaling consequences that affect cell phenotypes (e.g., cell death) in unanticipated ways. To map specific signaling consequences of SHP2 antagonism to phenotypes of interest, a data-driven computational model was constructed based on the paired signaling and phenotype data. Model predictions aided in identifying three signaling processes with implications for treating glioblastoma with SHP2 inhibitors. These included PTEN-dependent DNA damage repair in response to SHP2 inhibition, AKT-mediated bypass resistance in response to chronic SHP2 inhibition, and SHP2 control of hypoxia-inducible factor expression through multiple MAPKs. Model-generated hypotheses were validated in multiple glioblastoma cell lines, in mouse tumor xenografts, and through analysis of The Cancer Genome Atlas data. Collectively, these results suggest that in glioblastoma, SHP2 inhibitors antagonize some signaling processes more effectively than existing kinase inhibitors but can also limit the efficacy of other drugs when used in combination. SIGNIFICANCE: These findings demonstrate that allosteric SHP2 inhibitors have multivariate and context-dependent effects in glioblastoma that may make them useful components of some combination therapies, but not others.

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Cell Line, Tumor
  • DNA Repair / physiology
  • Data Science
  • Dimethyl Sulfoxide / therapeutic use
  • Drug Resistance, Neoplasm
  • Female
  • Gefitinib / therapeutic use
  • Glioblastoma / drug therapy*
  • Glioblastoma / enzymology
  • Heterografts
  • Humans
  • Indoles / therapeutic use
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Least-Squares Analysis
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Models, Biological
  • Neoplasm Transplantation
  • PTEN Phosphohydrolase / metabolism
  • Phenotype
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribonucleoproteins, Small Nuclear
  • Signal Transduction
  • Sulfones / therapeutic use
  • Temozolomide / therapeutic use
  • Transcription Factor AP-1 / metabolism
  • src Homology Domains


  • 5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • Ribonucleoproteins, Small Nuclear
  • SART1 protein, human
  • Sulfones
  • Transcription Factor AP-1
  • Proto-Oncogene Proteins c-akt
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Gefitinib
  • Temozolomide
  • Dimethyl Sulfoxide