Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia−Related Head and Neck Cancer
Published OnlineFirst January 31, 2020; DOI: 10.1158/1078-0432.CCR-19-1625 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer Helena Montanuy1, Agueda Martínez-Barriocanal2,3, Jose Antonio Casado4,5, Llorenc¸ Rovirosa1, Maria Jose Ramírez1,4,6, Rocío Nieto2, Carlos Carrascoso-Rubio4,5, Pau Riera6,7, Alan Gonzalez 8, Enrique Lerma7, Adriana Lasa4,6, Jordi Carreras-Puigvert9, Thomas Helleday9, Juan A. Bueren4,5, Diego Arango2,3, Jordi Minguillon 1,4,5, and Jordi Surralles 1,4,5 ABSTRACT ◥ Purpose: Fanconi anemia rare disease is characterized by bone two best candidates, gefitinib and afatinib, EGFR inhibitors marrow failure and a high predisposition to solid tumors, especially approved for non–small cell lung cancer (NSCLC), displayed head and neck squamous cell carcinoma (HNSCC). Patients with nontumor/tumor IC50 ratios of approximately 400 and approx- Fanconi anemia with HNSCC are not eligible for conventional imately 100 times, respectively. Neither gefitinib nor afatinib therapies due to high toxicity in healthy cells, predominantly activated the Fanconi anemia signaling pathway or induced hematotoxicity, and the only treatment currently available is sur- chromosomal fragility in Fanconi anemia cell lines. Importantly, gical resection. In this work, we searched and validated two already both drugs inhibited tumor growth in xenograft experiments in approved drugs as new potential therapies for HNSCC in patients immunodeficient mice using two Fanconi anemia patient– with Fanconi anemia. derived HNSCCs. Finally, in vivo toxicity studies in Fanca- Experimental Design: We conducted a high-content screening deficient mice showed that administration of gefitinib or afatinib of 3,802 drugs in a FANCA-deficient tumor cell line to identify was well-tolerated, displayed manageable side effects, no toxicity nongenotoxic drugs with cytotoxic/cytostatic activity.
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