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

Velina S. Atanasova, Celine Pourreyron, Mehdi Farshchian, Michael E. Lawler, Christian A. Brown, Stephen Watt, Sheila Wright, Michael Warkala, Christina Guttmann-Gruber, Josefina Pinon-Hofbauer, Ignacia Fuentes, Marco Prisco, Elham Rashidghamat, Cristina Has, Julio C. Salas-Alanis, Francis Palisson, Alain Hovnanian, John A. McGrath, Jemima Mellerio, Johann W. BauerAndrew P. South

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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.

Original languageEnglish
Pages (from-to)3384-3391
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number11
Early online date7 Mar 2019
DOIs
Publication statusPublished - Jun 2019

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    Atanasova, V. S., Pourreyron, C., Farshchian, M., Lawler, M. E., Brown, C. A., Watt, S., Wright, S., Warkala, M., Guttmann-Gruber, C., Pinon-Hofbauer, J., Fuentes, I., Prisco, M., Rashidghamat, E., Has, C., Salas-Alanis, J. C., Palisson, F., Hovnanian, A., McGrath, J. A., Mellerio, J., ... South, A. P. (2019). Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa–Associated Squamous Cell Carcinoma. Clinical Cancer Research, 25(11), 3384-3391. https://doi.org/10.1158/1078-0432.CCR-18-2661