Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNSCC) are urgently needed on relapse. Here, we described the relevance of targeting the ELR+CXCL cytokines receptors, CXCR1/2, for the treatment of these two cancer types. Methods: The relevance to patient treatment was evaluated by correlating the ELR+CXCL/CXCR1/2 levels to survival using online available data. We report herein the synthesis of new pharmacological inhibitors of CXCR1/2 with anti-proliferation/survival activity. The latter was evaluated with the XTT assay with leukemic, breast, RCC and HNSCC cell lines. Their relevance as an alternative treatment was tested on sunitinib- and cisplatin- resistant cells. The most efficient compound was then tested in a mouse model of RCC and HNSCC. Results: RCC and HNSCC expressed the highest amounts of CXCR1/2 of all cancers. High levels of ELR+CXCL cytokines (CXCL1, 2, 3, 5, 6, 7, 8) correlated to shorter survival. Among the 33 synthesized and tested molecules, compound C29 reduced ELR+CXCL/CXCR1/2-dependent proliferation and migration of endothelial cells. C29 exerted an anti-proliferation/survival activity on a panel of cancer cells including naive and resistant RCC and HNSCC cells. C29 reduced the growth of experimental RCC and HNSCC tumors by decreasing tumor cell proliferation, angiogenesis and ELR+/CXCL-mediated inflammation. Conclusion: Our study highlights the relevance of new CXCR1/2 inhibitors for the treatment of RCC or HNSCC as first-line treatment or at relapse on reference therapies.

Theranostics. 2019 Jul 09*** epublish ***

Maeva Dufies, Oleksandr Grytsai, Cyril Ronco, Oumar Camara, Damien Ambrosetti, Anaïs Hagege, Julien Parola, Lou Mateo, Marion Ayrault, Sandy Giuliano, Renaud Grépin, Nathalie Lagarde, Matthieu Montes, Patrick Auberger, Luc Demange, Rachid Benhida, Gilles Pagès

Centre Scientifique de Monaco, Biomedical Department, Principality of Monaco., Université Côte d’Azur, CNRS, Institut de Chimie de Nice UMR 7272, 06108, Nice, France., Université Côte d’Azur, Centre Hospitalier Universitaire (CHU) de Nice, Hôpital Pasteur, Department of Pathology, Nice, France., Université Côte d’Azur, CNRS UMR 7284 and INSERM U 1081, Institute for Research on Cancer and Aging (IRCAN), 28 Avenue de Valombrose, 06107 Nice, France., Centre Antoine Lacassagne, Nice, France., Université de Paris, CiTCoM, UMR 8038 CNRS, F-75006 Paris, France., Laboratoire GBCM EA7528, Conservatoire National des Arts et Métiers, 2 Rue Conté, 75003 Paris, France., Université Côte d’Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Bâtiment ARCHIMED, 151 Route de Saint-Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex 3, France.