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Biology of Human Tumors

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

Matthew A. Smith, Thomas Licata, Aliya Lakhani, Marileila Varella Garcia, Hans-Ulrich Schildhaus, Vincent Vuaroqueaux, Balazs Halmos, Alain C. Borczuk, Y. Ann Chen, Benjamin C. Creelan, Theresa A. Boyle and Eric B. Haura
Matthew A. Smith
Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
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Thomas Licata
Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
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Aliya Lakhani
Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
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Marileila Varella Garcia
University of Colorado, Denver, Colorado.
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Hans-Ulrich Schildhaus
Institute of Pathology University Hospital, Goettingen, Germany.
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Vincent Vuaroqueaux
Oncotest, Freiburg, Germany.
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Balazs Halmos
Department of Oncology, Montefiore/Albert Einstein Cancer Center, Bronx, New York.
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Alain C. Borczuk
Department of Pathology, Weill-Cornell Medicine, New York, New York.
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Y. Ann Chen
Department of Biostatistics, Moffitt Cancer Center, Tampa, Florida.
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Benjamin C. Creelan
Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
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Theresa A. Boyle
Department of Molecular Pathology, Moffitt Cancer Center, Tampa, Florida.
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Eric B. Haura
Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
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  • For correspondence: Eric.Haura@moffitt.org
DOI: 10.1158/1078-0432.CCR-16-3006
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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 Δexon14 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 Δexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Δexon14 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); 1–13. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received November 30, 2016.
  • Revision received May 1, 2017.
  • Accepted August 23, 2017.
  • ©2017 American Association for Cancer Research.
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Published OnlineFirst October 31, 2017
doi: 10.1158/1078-0432.CCR-16-3006

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MET–GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors
Matthew A. Smith, Thomas Licata, Aliya Lakhani, Marileila Varella Garcia, Hans-Ulrich Schildhaus, Vincent Vuaroqueaux, Balazs Halmos, Alain C. Borczuk, Y. Ann Chen, Benjamin C. Creelan, Theresa A. Boyle and Eric B. Haura
Clin Cancer Res October 31 2017 DOI: 10.1158/1078-0432.CCR-16-3006

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MET–GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors
Matthew A. Smith, Thomas Licata, Aliya Lakhani, Marileila Varella Garcia, Hans-Ulrich Schildhaus, Vincent Vuaroqueaux, Balazs Halmos, Alain C. Borczuk, Y. Ann Chen, Benjamin C. Creelan, Theresa A. Boyle and Eric B. Haura
Clin Cancer Res October 31 2017 DOI: 10.1158/1078-0432.CCR-16-3006
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