Combination of copanlisib with cetuximab improves tumor response in cetuximab-resistant patient-derived xenografts of head and neck cancer
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Konrad Klinghammer1, Oliver Politz2, Theresa Eder3,4, Raik Otto5, Jan-Dirk Raguse6, Andreas Albers7, Andreas Kaufmann8, Ingeborg Tinhofer3, Jens Hoffmann9, Ulrich Keller1 and Ulrich Keilholz10
1 Department of Hematology and Medical Oncology, Charité, Berlin, Germany
2 Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany
3 Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany
4 German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Berlin, Germany
5 WBI, Humboldt-Universität zu Berlin, Berlin, Germany
6 Department of Maxillio-Facial Surgery, Fachklinik Hornheide, Münster, Germany
7 Department of ENT, Charité, Berlin, Germany
8 Department of Gynaecology, Charité, Berlin, Germany
9 Experimental Pharmacology & Oncology GmbH, Berlin, Germany
10 Charité Comprehensive Cancer Center, Berlin, Germany
|Konrad Klinghammer,||email:||[email protected]|
Keywords: cetuximab; copanlisib; head and neck squamous cell carcinoma; HPV; patient-derived xenograft model
Received: June 06, 2020 Accepted: September 24, 2020 Published: October 13, 2020
Despite recent advances, the treatment of head and neck squamous cell carcinoma (HNSCC) remains an area of high unmet medical need. HNSCC is frequently associated with either amplification or mutational changes in the PI3K pathway, making PI3K an attractive target particularly in cetuximab-resistant tumors. Here, we explored the antitumor activity of the selective, pan-class I PI3K inhibitor copanlisib with predominant activity towards PI3Kα and δ in monotherapy and in combination with cetuximab using a mouse clinical trial set-up with 33 patient-derived xenograft (PDX) models with known HPV and PI3K mutational status and available data on cetuximab sensitivity. Treatment with copanlisib alone resulted in moderate antitumor activity with 12/33 PDX models showing either tumor stabilization or regression. Combination treatment with copanlisib and cetuximab was superior to either of the monotherapies alone in the majority of the models (21/33), and the effect was particularly pronounced in cetuximab-resistant tumors (14/16). While no correlation was observed between PI3K mutation status and response to either cetuximab or copanlisib, increased PI3K signaling activity evaluated through gene expression profiling showed a positive correlation with response to copanlisib. Together, these data support further investigation of PI3K inhibition in HNSCC and suggests gene expression patterns associated with PI3K signaling as a potential biomarker for predicting treatment responses.
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