Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib

// Maria Serova 1, 2, 3 , Annemilai Tijeras-Raballand 1, 2, 3 , Celia Dos Santos 1, 2, 3 , Matthieu Martinet 1 , Cindy Neuzillet 2, 3 , Alfred Lopez 4 , Dianne C. Mitchell 4 , Brad A. Bryan 4 , Guillaume Gapihan 3, 5 , Anne Janin 3, 5 , Guilhem Bousquet 5, 6 , Maria Eugenia Riveiro 2, 3 , Ivan Bieche 7 , Sandrine Faivre 2, 3 , Eric Raymond 2, 3, * , Armand de Gramont 1, 3, 5, * 1 AAREC Filia Research, Boulogne-Billancourt, France 2 Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France 3 INSERM, Paris, France 4 Department of Biomedical Sciences, Center of Emphasis in Cancer Research at The Paul Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA 5 Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris, France 6 Department of Medical Oncology, Avicenne University Hospital (APHP- PRES Paris 13 University), Bobigny, France 7 Laboratory of Oncogenetics, Institut Curie, Hopital Rene Huguenin, St-Cloud, France * These authors contributed equally to this work Correspondence to: Eric Raymond, email: eric.raymond@aphp.fr Keywords: everolimus, sunitinib, renal cell carcinoma, angiogenesis, differentiation Received: February 22, 2016      Accepted: May 04, 2016      Published: May 21, 2016 ABSTRACT Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo . Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm.