KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.
Thomas Mühlenberg, Johanna Falkenhorst, Tom Schulz, Benjamin S Fletcher, Alina Teuber, Dawid Krzeciesa, Isabella Klooster, Meijun Lundberg, Lydia Wilson, Jonas Lategahn, Margaret von Mehren, Susanne Grunewald, Alicia Isabell Tüns, Eva Wardelmann, Jason K Sicklick, Mehdi Brahmi, César Serrano, Hans-Ulrich Schildhaus, Sonja Sievers, Jürgen Treckmann, Michael C Heinrich, Chandrajit P Raut, Wen-Bin Ou, Adrian Marino-Enriquez, Suzanne George, Daniel Rauh, Jonathan A Fletcher, Sebastian Bauer
Author Information
Thomas Mühlenberg: Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. ORCID
Johanna Falkenhorst: Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. ORCID
Tom Schulz: Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. ORCID
Benjamin S Fletcher: Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. ORCID
Alina Teuber: Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. ORCID
Dawid Krzeciesa: Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
Isabella Klooster: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ORCID
Meijun Lundberg: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ORCID
Lydia Wilson: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Jonas Lategahn: Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. ORCID
Margaret von Mehren: Department of Hematology and Oncology, Fox Chase Cancer Center, Temple Health System, University, Philadelphia, PA. ORCID
Susanne Grunewald: Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
Alicia Isabell Tüns: Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany. ORCID
Eva Wardelmann: Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany.
Jason K Sicklick: Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, CA. ORCID
Mehdi Brahmi: Centre Leon Berard, Medical Oncology, Lyon, France. ORCID
César Serrano: Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Hans-Ulrich Schildhaus: University Hospital Essen, Institute of Pathology, Essen, Germany. ORCID
Sonja Sievers: Compound Management and Screening Center, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
Jürgen Treckmann: University of Duisburg-Essen, Medical School, Department of Visceral and Transplantation Surgery, Essen, Germany.
Michael C Heinrich: Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, OR. ORCID
Chandrajit P Raut: Department of Surgery, Brigham and Women's Hospital, Boston, MA. ORCID
Wen-Bin Ou: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ORCID
Adrian Marino-Enriquez: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ORCID
Suzanne George: Dana-Farber Cancer Institute, Medical Oncology, Boston, MA. ORCID
Daniel Rauh: Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany. ORCID
Jonathan A Fletcher: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. ORCID
Sebastian Bauer: Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany. ORCID
PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.
References
Cancer Discov. 2021 Jan;11(1):108-125
[PMID: 32972961]
