TY - JOUR
T1 - Identification of rigosertib for the treatment of recessive dystrophic epidermolysis bullosa–associated squamous cell carcinoma
AU - Atanasova, Velina S.
AU - Pourreyron, Celine
AU - Farshchian, Mehdi
AU - Lawler, Michael
AU - Brown, Christian A.
AU - Watt, Stephen A.
AU - Wright, Sheila
AU - Warkala, Michael
AU - Guttmann-Gruber, Christina
AU - Hofbauer, Josefina Piñon
AU - Fuentes, Ignacia
AU - Prisco, Marco
AU - Rashidghamat, Elham
AU - Has, Cristina
AU - Salas-Alanis, Julio C.
AU - Palisson, Francis
AU - Hovnanian, Alain
AU - McGrath, John A.
AU - Mellerio, Jemima E.
AU - Bauer, Johann W.
AU - South, Andrew P.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066608395&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066608395&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-2661
DO - 10.1158/1078-0432.CCR-18-2661
M3 - Article
C2 - 30846478
AN - SCOPUS:85066608395
SN - 1078-0432
VL - 25
SP - 3384
EP - 3391
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -