1. Ponatinib Shows Potent Antitumor Activity in Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) through Multikinase Inhibition
- Author
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Patrick Pirrotte, Anthony N. Karnezis, Jeff Kiefer, Jeffrey M. Trent, Krystal A. Orlando, Michael B. Major, Bernard E. Weissman, David G. Huntsman, Megan Washington, Yemin Wang, Nanyun Tang, Ritin Sharma, Elizabeth A. Raupach, Emily M. Cousins, Victoria Zismann, Barbara C. Vanderhyden, Pilar Ramos, Winnie S. Liang, Hongwei Yin, Praveen Nair, William P.D. Hendricks, Chris Sereduk, Salvatore Facista, Aleksandar Sekulic, Ralf Hass, and Jessica D. Lang
- Subjects
0301 basic medicine ,Cancer Research ,Cell ,Pharmacology ,Receptor tyrosine kinase ,law.invention ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,law ,Protein Interaction Mapping ,Protein Interaction Maps ,Carcinoma, Small Cell ,RNA, Small Interfering ,Cancer ,Ovarian Neoplasms ,0303 health sciences ,Tumor ,biology ,Kinase ,Ponatinib ,Imidazoles ,Ovarian Cancer ,3. Good health ,Pyridazines ,medicine.anatomical_structure ,Oncology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,SMARCA4 ,Female ,Development of treatments and therapeutic interventions ,Biotechnology ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Small Interfering ,Small-cell carcinoma ,Article ,Cell Line ,03 medical and health sciences ,Rare Diseases ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Oncology & Carcinogenesis ,Protein Kinase Inhibitors ,030304 developmental biology ,Animal ,business.industry ,Carcinoma ,Computational Biology ,Receptor Protein-Tyrosine Kinases ,Small Cell ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Orphan Drug ,Good Health and Well Being ,030104 developmental biology ,chemistry ,Disease Models ,Cancer research ,biology.protein ,RNA ,Suppressor ,business ,Ovarian cancer - Abstract
Structured AbstractPurpose: 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 InformationThis 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.
- Published
- 2017