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MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors.

ABSTRACT: Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a ?exon14 MET splice variant.Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with ?exon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with ?exon14 MET lacking MET gene amplification.Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084-96. ©2017 AACR.

SUBMITTER: Smith MA

PROVIDER: S-EPMC5833309 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors.

Smith Matthew A MA Licata Thomas T Lakhani Aliya A Garcia Marileila Varella MV Schildhaus Hans-Ulrich HU Vuaroqueaux Vincent V Halmos Balazs B Borczuk Alain C AC Chen Y Ann YA Creelan Benjamin C BC Boyle Theresa A TA Haura Eric B EB

Clinical cancer research : an official journal of the American Association for Cancer Research 20170829 22

<b>Purpose:</b> Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.<b>Experimental Design:</b> We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in ...[more]

PMID: 28855353

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Project description:BackgroundDeregulation of receptor tyrosine kinases (RTK) contributes to the initiation and progression of intestinal-derived epithelial cancers, including colorectal cancer (CRC). However, the roles of the proximal signaling molecules engaged by RTKs in different oncogenic functions of CRC remain unclear.MethodsHerein, the functional impact of expressing variant forms of the oncogenic Met receptor (Tpr-Met) that selectively recruit the adaptor proteins Grb2 or Shc was investigated in a model derived from normal intestinal epithelial cells (IEC-6). An RNA interference (RNAi) approach was used to define the requirement of Grb2 or Shc in Tpr-Met-transformed IEC-6 cells. Since Grb2 and Shc couple RTKs to the activation of the Ras/MEK/Erk and PI3K/Akt pathways, Erk and Akt phosphorylation/activation states were monitored in transformed IEC-6 cells, and a pharmacological approach was employed to provide insights into the roles of these pathways in oncogenic processes evoked by activated Met, and downstream of Grb2 and Shc.ResultsWe show, for the first time, that constitutive activation of either Grb2 or Shc signals in IEC-6 cells, promotes morphological transformation associated with down-regulation of E-cadherin, as well as increased cell growth, loss of growth contact inhibition, anchorage-independent growth, and resistance to serum deprivation and anoikis. Oncogenic activation of Met was revealed to induce morphological transformation, E-cadherin down-regulation, and protection against anoikis by mechanisms dependent on Grb2, while Shc was shown to be partly required for enhanced cell growth. The coupling of activated Met to the Ras/MEK/Erk and PI3K/Akt pathways, and the sustained engagement of Grb2 or Shc in IECs, was shown to trigger negative feedback, limiting the extent of activation of these pathways. Nonetheless, morphological alterations and E-cadherin down-regulation induced by the oncogenic Tpr-Met, and by Grb2 or Shc signals, were blocked by MEK, but not PI3K, inhibitors while the enhanced growth and resistance to anoikis induced by Tpr-Met were nearly abolished by co-treatment with both inhibitors.ConclusionOverall, these results identify Grb2 and Shc as central signaling effectors of Met-driven progression of intestinal epithelial-derived cancers. Notably, they suggest that Grb2 may represent a promising target for the design of novel CRC therapies.

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MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors.

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MET-GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors.

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