Identification of rigosertib for the treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma

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

研究成果: Article同行評審

27 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)3384-3391
頁數8
期刊Clinical Cancer Research
25
發行號11
DOIs
出版狀態Published - 2019 6月 1

All Science Journal Classification (ASJC) codes

  • 一般醫學

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