Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma.
Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy.



We used whole-exome and transcriptome sequencing to identify a KIT exon 11 mutation (c.1733_1735del, p.D579del) as potentially druggable target in this patient and carried out cancer hotspot panel sequencing to detect secondary resistance-conferring mutations in KIT. Furthermore, as a step towards clinical exploitation of the recently described signatures of mutational processes in cancer genomes, we established and applied a novel bioinformatics algorithm that enables supervised analysis of the mutational catalogs of individual tumors.



Molecularly guided treatment with imatinib in analogy to the management of gastrointestinal stromal tumor (GIST) resulted in a dramatic and durable response with remission of nearly all tumor manifestations, indicating a dominant driver function of mutant KIT in this tumor. KIT dependency was further validated by a secondary KIT exon 17 mutation (c.2459_2462delATTCinsG, p.D820_S821delinsG) that was detected upon tumor progression after 10 months of imatinib treatment and provided a rationale for salvage therapy with regorafenib, which has activity against KIT exon 11/17 mutant GIST.



These observations highlight the potential of unbiased genomic profiling for uncovering the vulnerabilities of individual malignancies, particularly in rare and unclassifiable tumors, and underscore that KIT exon 11 mutations represent tractable therapeutic targets across different histologies.
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
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Dieter
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
C
C
Heining
Institute of Pathology, Erlangen University Hospital, Erlangen, Germany.
A
A
Agaimy
Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.|Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, and BioQuant, Heidelberg University, Heidelberg, Germany.|Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
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D
Huebschmann
Division of Radiology, DKFZ, Heidelberg, Germany.
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D
Bonekamp
German Cancer Consortium (DKTK), Heidelberg, Germany.|Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
B
B
Hutter
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medical Oncology, NCT Heidelberg, and Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.
K R
KR
Ehrenberg
German Cancer Consortium (DKTK), Heidelberg, Germany.|Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
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M
Fröhlich
Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.
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M
Schlesner
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
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C
Scholl
Division of Radiology, DKFZ, Heidelberg, Germany.
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HP
Schlemmer
Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
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S
Wolf
Department of Medical Oncology, NCT Heidelberg, and Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.
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A
Mavratzas
Department of Neurosurgery, Heidelberg University Hospital, Heidelberg, Germany.
C S
CS
Jung
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
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S
Gröschel
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany.
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C
von Kalle
Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.|Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, and BioQuant, Heidelberg University, Heidelberg, Germany.|DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany.
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R
Eils
German Cancer Consortium (DKTK), Heidelberg, Germany.|Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
B
B
Brors
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
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R
Penzel
Institute of Pathology, Heidelberg University, Heidelberg, Germany.
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M
Kriegsmann
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
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DE
Reuss
German Cancer Consortium (DKTK), Heidelberg, Germany.|Institute of Pathology, Heidelberg University, Heidelberg, Germany.
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P
Schirmacher
Institute of Pathology, Heidelberg University, Heidelberg, Germany.|Department of Pathology, Center for Integrated Diagnostics, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
A
A
Stenzinger
Department of Otorhinolaryngology, Heidelberg University Hospital, Heidelberg, Germany.
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PA
Federspil
Institute of Pathology, Heidelberg University, Heidelberg, Germany.|Institute of Pathology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|DKTK, Munich, Germany.
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W
Weichert
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
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H
Glimm
Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.
S
S
Fröhling
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D010255:Paranasal Sinus Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
cancer genomics; head and neck cancer; precision oncology