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

Abstract

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.

Gli-1/PI3K/AKT/NF-kB pathway mediates resistance to radiation and is a target for reversion of responses in refractory acute myeloid leukemia cells

“…One possible pathway is PI3K/AKT that is implicated in radioresistance [26, 27]. Although the detailed mechanisms of Hh signaling effects on the PI3K/AKT pathway are still unclear, several studies have shown that the activity of AKT can be reduced by Hh inhibitors [41, 42]. Fu et al [43] reported that Hh protein promotes cell proliferation, migration, and vascular endothelial growth factor production through the PI3K/AKT pathway.…”

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

“…It is also being studied in the context of other cancers, like gastric and prostate cancer, and is currently undergoing phase I and II trials. Another FDA-approved SMO antagonist is NVP-LDE225 (Erismodegib or sonidegib), used for advanced cases of basal cell carcinomas (118). Erismodegib is also being studied in phase I and II clinical trials for other cancer types.…”

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

“…It acts by binding to and inhibiting the activity of the SMO transmembrane protein, resulting in complete suppression of GLI and tumor regression [18]. In vitro studies and in animal models have demonstrated the inhibition of Hh signaling and the antitumor activity of sonidegib; the oral administration of sonidegib in mouse models resulted in complete suppression of glioma-associated oncogene homolog 1 (GLI1) and tumor regression, suggesting targeted inhibition of hedgehog signaling [19,20]. Several preclinical studies have shown the high tissue penetration, including blood and brain barrier, and good oral bioavailability of this molecule [21].…”