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

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dc.contributor.authorAtanasova, Velina S.
dc.contributor.authorPourreyron, Celine
dc.contributor.authorFarshchian, Mehdi
dc.contributor.authorChristian A., Brown IV
dc.contributor.authorWatt, Stephen A.
dc.contributor.authorWright, Sheila
dc.contributor.authorWarkala, Michael
dc.contributor.authorGuttmann-Gruber, Christina
dc.contributor.authorPiñón Hofbauer, Josefina
dc.contributor.authorFuentes, Ignacia
dc.contributor.authorPrisco, Marco
dc.contributor.authorRashidghamat, Elham
dc.contributor.authorHas, Cristina
dc.contributor.authorPalisson, Francis
dc.contributor.authorHovnanian, Alain
dc.contributor.authorMcGrath, John A.
dc.contributor.authorMellerio, Jemima E.
dc.contributor.authorBauer, Johann
dc.contributor.authorSouth, Andrew P.
dc.date.accessioned2020-04-02T19:37:13Z
dc.date.available2020-04-02T19:37:13Z
dc.date.issued2019
dc.description.abstractPurpose: 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. Translational Relevance Collectively, our data support a clinical trial of rigosertib for treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma, an inherently aggressive subtype of squamous cell carcinoma with extremely low 5-year survival. Currently, there are no effective treatments for this devastating cancer, and often times, initial squamous cell carcinoma will recur and readily metastasize; any effective systemic therapy that reduces tumor burden will improve quality of life in this patient population.
dc.format.extent30 p.
dc.identifier.citationClinical Cancer Research 2019 Jun 1;25(11):3384-3391
dc.identifier.urihttp://hdl.handle.net/11447/3208
dc.identifier.urihttps://doi.org/10.1158/1078-0432.CCR-18-2661
dc.language.isoen
dc.subjectAKT
dc.subjectCRAF
dc.subjectRAS
dc.subjectSquamous cell carcinoma
dc.subjectPLK1
dc.subjectRecessive dystrophic epidermolysis bullosa
dc.titleIdentification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma.
dc.typeArticle

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