New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments

Maeva Dufies (1) , Oleksandr Grytsai (2) , Cyril Ronco (2) , Oumar Camara (2) , Damien Ambrosetti (3, 4) , Anaïs Hagege (4) , Julien Parola (5) , Lou Mateo (2) , Marion Ayrault (6) , Sandy Giuliano (4) , Renaud Grépin (1) , Nathalie Lagarde (7) , Matthieu Montes (7) , Patrick Auberger (8) , Luc Demange (2, 6) , Rachid Benhida (2) , Gilles Pagès (1, 4)

1 CSM - Centre Scientifique de Monaco
2 ICN - Institut de Chimie de Nice
3 CHU - Hôpital Pasteur [Nice]
4 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
5 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
6 CiTCoM - UMR 8038 - Cibles Thérapeutiques et conception de médicaments
7 GBCM - Laboratoire Génomique, bioinformatique et chimie moléculaire
8 C3M - Centre méditerranéen de médecine moléculaire

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.

Keywords: ELR + CXCL cytokines; Clear cell Renal Cell Carcinoma; Head and Neck Squamous Cell Carcinoma; CXCR1/2 inhibitor; angiogenesis

Domains: Cancer; Pharmacology

Maeva Dufies, Oleksandr Grytsai, Cyril Ronco, Oumar Camara, Damien Ambrosetti, et al.. New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments. Theranostics, 2019, 9 (18), pp.5332-5346. ⟨10.7150/thno.34681⟩. ⟨hal-02308756⟩