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Molecular Cancer Therapeutics

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Small Molecule Therapeutics

KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors — TORC1/2 Inhibition as Salvage Strategy

Thomas Mühlenberg, Julia Ketzer, Michael C. Heinrich, Susanne Grunewald, Adrian Marino-Enriquez, Marcel Trautmann, Wolfgang Hartmann, Eva Wardelmann, Jürgen Treckmann, Karl Worm, Stefanie Bertram, Thomas Herold, Hans-Ulrich Schildhaus, Hanno Glimm, Albrecht Stenzinger, Benedikt Brors, Peter Horak, Peter Hohenberger, Stefan Fröhling, Jonathan A. Fletcher and Sebastian Bauer
Thomas Mühlenberg
Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.German Cancer Consortium (DKTK), Heidelberg, Germany.
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  • ORCID record for Thomas Mühlenberg
  • For correspondence: thomas.muehlenberg@uk-essen.de Sebastian.bauer@uk-essen.de
Julia Ketzer
Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.German Cancer Consortium (DKTK), Heidelberg, Germany.
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Michael C. Heinrich
Portland VA Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
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  • ORCID record for Michael C. Heinrich
Susanne Grunewald
Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.German Cancer Consortium (DKTK), Heidelberg, Germany.
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Adrian Marino-Enriquez
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Marcel Trautmann
Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
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  • ORCID record for Marcel Trautmann
Wolfgang Hartmann
Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
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Eva Wardelmann
Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
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Jürgen Treckmann
Department of Visceral and Transplant Surgery, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
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Karl Worm
Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Germany.
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Stefanie Bertram
Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Germany.
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Thomas Herold
German Cancer Consortium (DKTK), Heidelberg, Germany.Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Germany.
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Hans-Ulrich Schildhaus
Institute of Pathology, Universitätsmedizin Göttingen, Göttingen, Germany.
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Hanno Glimm
German Cancer Consortium (DKTK), Heidelberg, Germany.Department of Translational Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden University Hospital, Dresden, Germany.
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Albrecht Stenzinger
German Cancer Consortium (DKTK), Heidelberg, Germany.Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
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Benedikt Brors
German Cancer Consortium (DKTK), Heidelberg, Germany.Department of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg University, Heidelberg, Germany.
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Peter Horak
German Cancer Consortium (DKTK), Heidelberg, Germany.Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany.
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Peter Hohenberger
Mannheim, University Medical Center, Mannheim, Germany.
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Stefan Fröhling
German Cancer Consortium (DKTK), Heidelberg, Germany.Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg University Hospital, Heidelberg, Germany.
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Jonathan A. Fletcher
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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Sebastian Bauer
Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.German Cancer Consortium (DKTK), Heidelberg, Germany.
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  • For correspondence: thomas.muehlenberg@uk-essen.de Sebastian.bauer@uk-essen.de
DOI: 10.1158/1535-7163.MCT-18-1224
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Abstract

Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients—adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2. We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT–related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2019;18:1–12

  • Received October 26, 2018.
  • Revision received January 21, 2019.
  • Accepted July 8, 2019.
  • Published first July 15, 2019.
  • ©2019 American Association for Cancer Research.

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Published OnlineFirst October 9, 2019
doi: 10.1158/1535-7163.MCT-18-1224

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KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors — TORC1/2 Inhibition as Salvage Strategy
Thomas Mühlenberg, Julia Ketzer, Michael C. Heinrich, Susanne Grunewald, Adrian Marino-Enriquez, Marcel Trautmann, Wolfgang Hartmann, Eva Wardelmann, Jürgen Treckmann, Karl Worm, Stefanie Bertram, Thomas Herold, Hans-Ulrich Schildhaus, Hanno Glimm, Albrecht Stenzinger, Benedikt Brors, Peter Horak, Peter Hohenberger, Stefan Fröhling, Jonathan A. Fletcher and Sebastian Bauer
Mol Cancer Ther October 9 2019 DOI: 10.1158/1535-7163.MCT-18-1224

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KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors — TORC1/2 Inhibition as Salvage Strategy
Thomas Mühlenberg, Julia Ketzer, Michael C. Heinrich, Susanne Grunewald, Adrian Marino-Enriquez, Marcel Trautmann, Wolfgang Hartmann, Eva Wardelmann, Jürgen Treckmann, Karl Worm, Stefanie Bertram, Thomas Herold, Hans-Ulrich Schildhaus, Hanno Glimm, Albrecht Stenzinger, Benedikt Brors, Peter Horak, Peter Hohenberger, Stefan Fröhling, Jonathan A. Fletcher and Sebastian Bauer
Mol Cancer Ther October 9 2019 DOI: 10.1158/1535-7163.MCT-18-1224
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Molecular Cancer Therapeutics
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