Identification of a novel ATM inhibitor with cancer cell specific radiosensitization activity

Abstract

// Amy J.C. Dohmen 1 , Xiaohang Qiao 2 , Anja Duursma 2 , Ruud H. Wijdeven 2 , Cor Lieftink 3 , Floor Hageman 4 , Ben Morris 3 , Pasi Halonen 3 , Conchita Vens 4 , Michiel W.M. van den Brekel 1, 5 , Huib Ovaa 6, 7 , Jacques Neefjes 6, 7 and Charlotte L. Zuur 1, 5 1 Department of Head and Neck Oncology and Surgery, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands 2 Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3 NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands 4 Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands 5 Department of Oral and Maxillofacial Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands 6 Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 7 Department of Chemical Immunology, Leiden University Medical Center, Leiden, The Netherlands Correspondence to: Charlotte L. Zuur, email: [email protected] Keywords: cancer, radiotherapy, radiosensitizer, ATM, DNA damage response Received: December 21, 2016      Accepted: April 26, 2017      Published: May 19, 2017 ABSTRACT Treatment of advanced head and neck squamous cell carcinoma (HNSCC) is plagued by low survival and high recurrence rates, despite multimodal therapies. Presently, cisplatin or cetuximab is used in combination with radiotherapy which has resulted in minor survival benefits but increased severe toxicities relative to RT alone. This underscores the urgent need for improved tumor-specific radiosensitizers for better control with lower toxicities. In a small molecule screen targeting kinases, performed on three HNSCC cell lines, we identified GSK635416A as a novel radiosensitizer. The extent of radiosensitization by GSK635416A outperformed the radiosensitization observed with cisplatin and cetuximab in our models, while exhibiting virtually no cytotoxicity in the absence of radiation and in normal fibroblast cells. Radiation induced phosphorylation of ATM was inhibited by GSK635416A. GSK63541A increased DNA double strand breaks after radiation and GSK63541A mediated radiosensitization was lacking in ATM-mutated cells thereby further supporting the ATM inhibiting properties of GSK63541A. As a novel ATM inhibitor with highly selective radiosensitizing activity, GSK635416A holds promise as a lead in the development of drugs active in potentiating radiotherapy for HNSCC and other cancer types.