Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells

Background: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is...

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Published in:	British journal of cancer Vol. 111; no. 6; pp. 1168 - 1179
Main Authors:	D’Amato, C, Rosa, R, Marciano, R, D’Amato, V, Formisano, L, Nappi, L, Raimondo, L, Di Mauro, C, Servetto, A, Fulciniti, F, Cipolletta, A, Bianco, C, Ciardiello, F, Veneziani, B M, De Placido, S, Bianco, R
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 09-09-2014 Nature Publishing Group
Subjects:	631/154/309/436/2388 631/67/1059/99 631/67/589/1588/1351 631/80/86 Actin Cytoskeleton - ultrastructure Actins - ultrastructure Animals Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - pharmacology Biological and medical sciences Biomedical and Life Sciences Biomedicine Biphenyl Compounds - administration & dosage Cancer Research Cancer therapies Carcinoma, Renal Cell - drug therapy Carcinoma, Renal Cell - secondary Cell growth Cell Line, Tumor Cell Movement - drug effects Cell Proliferation - drug effects Drug Resistance Drug Synergism Epidemiology Everolimus Genes Hedgehog Proteins - metabolism Humans Hypoxia Indoles - administration & dosage Inhibitory Concentration 50 Kidney cancer Kidney Neoplasms - drug therapy Kidney Neoplasms - pathology Kidneys Kinases Kruppel-Like Transcription Factors - metabolism Ligands Lung Neoplasms - secondary Medical sciences Metastasis Mice Mice, Inbred BALB C Mice, Nude Mitogen-Activated Protein Kinases - metabolism Molecular Medicine Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neoplasm Micrometastasis - drug therapy Nephrology. Urinary tract diseases Nuclear Proteins - metabolism Oncology Paxillin - metabolism Paxillin - ultrastructure Proto-Oncogene Proteins c-akt - metabolism Pyridines - administration & dosage Pyrroles - administration & dosage Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, G-Protein-Coupled - metabolism Ribosomal Protein S6 Kinases, 70-kDa - metabolism Signal Transduction - drug effects Sirolimus - administration & dosage Sirolimus - analogs & derivatives Smoothened Receptor Transcription Factors - metabolism Translational Therapeutics Tumor Burden - drug effects Tumors Tumors of the urinary system Vascular endothelial growth factor Xenograft Model Antitumor Assays Zinc Finger Protein GLI1 Zinc Finger Protein Gli2 Italy sunitinib resistance Hedgehog RCC NVP-LDE225 Antineoplastic agent Carcinoma Growth Tumorous infiltration Metastasis Sunitinib Cancerology Erismodegib Grawitz tumor Inhibition Antiangiogenic agent Protein-tyrosine kinase Cell Kidney disease Human Urinary system disease Enzyme Tyrosine kinase inhibitor Transferases Enzyme inhibitor Malignant tumor Invasion Resistance Hedgehog protein Kidney cancer Multikinase inhibitor Cancer
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Summary:	Background: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth. Methods: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo . To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib – a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. Results: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. Conclusions: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.
ISSN:	0007-0920 1532-1827
DOI:	10.1038/bjc.2014.421