RT Journal Article
SR Electronic
T1 Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multi-kinase inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 159905
DO 10.1101/159905
A1 Jessica D. Lang
A1 William P. D. Hendricks
A1 Holly Yin
A1 Jeffrey Kiefer
A1 Pilar Ramos
A1 Ritin Sharma
A1 Patrick Pirrotte
A1 Elizabeth A. Raupach
A1 Chris Sereduk
A1 Nanyun Tang
A1 Winnie Liang
A1 Megan Washington
A1 Salvatore J. Facista
A1 Victoria L. Zismann
A1 Emily M. Cousins
A1 Michael B. Major
A1 Yemin Wang
A1 Anthony N. Karnezis
A1 Krystal A. Orlando
A1 Aleksandar Sekulic
A1 Ralf Hass
A1 Barbara Vanderhyden
A1 Kesavannair Praveen
A1 Bernard E. Weissman
A1 David G. Huntsman
A1 Jeffrey M. Trent
YR 2017
UL http://biorxiv.org/content/early/2017/07/06/159905.abstract
AB Purpose: Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors inactivated in ∼20% of all cancers. Yet, few targeted treatments for SWI/SNF-mutant cancers exist. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits, SMARCA4 and SMARCA2. Given poor two-year survival rates for these women, a great need exists for effective targeted therapies.Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches comprehensively profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two PDX models and one cell line xenograft model of SCCOHT.Results: FGFRs and PDGFRs were overlapping hits between screens and the receptor tyrosine kinase (RTK) family was enriched in the siRNA screen hits. Evaluation of eleven RTK inhibitors in three SCCOHT cell lines identified ponatinib, an inhibitor of multiple RTKs, as the most effective clinically approved agent. Proteomics approaches confirmed inhibition of known targets of ponatinib and more than 20 non-canonical ponatinib targets. Ponatinib also delayed tumor doubling time 4-fold in SCCOHT-1 xenografts and reducing final tumor volumes in two SCCOHT patient-derived xenograft (PDX) models by 58.6% and 42.5%.Conclusion: Ponatinib is an effective agent for SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.Additional Information This work was supported by research funds from the Canadian Cancer Society Research Institute 34 (#703458, D.G.H.), the National Institutes of Health (R01 CA195670-01, B.E.W., D.G.H., and 35 J.M.T., and T32 HL007106-39 to E.M.C), the Terry Fox Research Institute Initiative New Frontiers Program in Cancer (#1021, D.G.H.), the British Columbia Cancer Foundation (D.G.H.), the VGH & UBC Foundation (D.G.H.), the Anne Rita Monahan Foundation (P.R.), the Marsha Rivkin Center for Ovarian Cancer Research (J.M.T.), the Ovarian Cancer Alliance of Arizona (J.M.T.), the Small Cell Ovarian Cancer Foundation (P.R., J.D.L., B.V., and J.M.T.), and philanthropic support to the TGen Foundation (J.M.T.).COI disclosure statement: The authors declare no potential conflicts of interest.