Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma

Abstract

Purpose: Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need. Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo. Results: ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib. Conclusions: These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.

Molecular Therapeutics in Development for Epidermolysis Bullosa: Update 2020

“…Although the drug was well-tolerated by 20 patients, no further studies were conducted. Preclinical work identified the potential of the multikinase inhibitor rigosertib, an experimental therapeutic in phase III trials for treatment of myelodysplastic syndrome and RDEB SCC [90]. In cell culture and animal studies, rigosertib induced apoptosis in RDEB SCC without adversely affecting non-SCC RDEB epidermal keratinocytes.…”

Targeting the Jak/Signal Transducer and Activator of Transcription 3 Pathway with Ruxolitinib in a Mouse Model of Recessive Dystrophic Epidermolysis Bullosa–Squamous Cell Carcinoma

“…Animals that were grafted with RDEB patient-derived cSCCs and FB developed tumors within 2-3 weeks post-grafting with characteristic morphological features of human RDEB-cSCCs, as shown by H&E and immunofluorescence (IF) staining (Fig 1 b, c, d). Several studies have previously reported tumor xenograft mouse models using multiple RDEB SCC cells lines, zebrafish models and organ culture graft models for RDEB (Atanasova et al, 2019;Dayal et al, 2020;Martins et al, 2016;Watt et al, 2011). The concept of grafting skin equivalents onto immunodeficient mice has been reported previously (Breitkreutz et al, 1998;Martins et al, 2016;Willhauck et al, 2007).…”

Small molecule drug development for rare genodermatoses – evaluation of the current status in epidermolysis bullosa

“…Rigosertib: Squamous cell carcinomas (SCC), one of the most threatening co-pathologies in RDEB, is treated with Rigosertib, a polo-like kinase (PLK)-1 inhibitor leading to apoptosis in cancer cells [86]. Oral and i.v.…”