ABSTRACT
Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Drug Resistance, Neoplasm , Kidney Neoplasms/genetics , Mutation , Animals , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/metabolism , Cell Line, Tumor , Exons , Female , Gene Expression Regulation, Neoplastic , Humans , Kidney Neoplasms/metabolism , Mice , Neoplasm Transplantation , Sequence Analysis, DNA , SunitinibABSTRACT
Laparoscopy has been widely used to repair anorectal malformations (ARMs) by paediatric surgeons in an attempt to be less invasive, offer better cosmetic results, enable a faster return of bowel function, decrease length of hospital stay and pain, and lately to improve functional results. Robotic technology assists the paediatric surgeon by increasing dexterity and precision of movement with a robotic wrist-like mechanism that allows up to 90° of articulation and 7° of freedom. This is important in ARM surgery, where the dissection of the fistula and the pull-through of the rectum into the muscular complex are crucial to achieve continence in future.