Abstract NTOC-090: TARGETING AND EFFICACY OF THE RECEPTOR TYROSINE KINASE INHIBITOR PONATINIB IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE, WORKS THROUGH INHIBITION OF PLATELET DERIVED GROWTH FACTOR RECEPTOR (PDGFR)
Authors: Lang Jessica D. , Hendricks William , Ramos Pilar , Yin Holly , Sereduk Chris , Kiefer Jeffrey , Wang Yemin , Karnezis Anthony N. , Weissman Bernard , Huntsman David , Trent Jeffrey 
Published: June 2017

The work that will be presented strongly suggests the identification of a unique vulnerability of Small Cell Carcinoma of the Ovary-Hypercalcemic Type (SCCOHT) to PDGFR inhibition. SCCOHT is an aggressive subtype of ovarian cancer afflicting young women and children with fewer than 35% of patients surviving two years after diagnosis. Currently, these patients must endure high dose chemotherapy because no effective targeted therapies have been identified. We previously demonstrated that these tumors are driven by inactivating mutations in SMARCA4, one of two ATPases in the SWI/SNF chromatin-remodeling complex. In addition, we have also shown that SCCOHT lacks expression of the alternative SWI/SNF ATPase, SMARCA2. SWI/SNF is a key tumor suppressor complex in diverse cancers and its members are mutationally inactivated in up to 50% of other ovarian cancer subtypes. However, no therapeutic approaches selective for SWI/SNF-dysregulation in cancers are routinely used.

We have now found through multiomic (DNA/RNA), pathway analysis, immunohistochemistry and functional studies in SCCOHT tumors and cell lines that SMARCA4 loss correlates with increased expression of receptor tyrosine kinases (RTKs) including the platelet derived growth factor receptors (PDGRs). Through integration of high-throughput RNA interference and drug screens in SCCOHT cell lines we have also identified sensitivity to RTK knockdown and inhibitors such as ponatinib. These data corroborate prior studies showing RTK dependence in rhabdoid tumors, rare cancers that are also driven by mutations in the SWI/SNF complex. As ponatinib is approved for cancer treatment and showed great potency, we tested this agent in two patient-derived xenograft (PDX) models of SCCOHT. Ponatinib significantly reduced tumor growth in both models. Of the known ponatinib targets, PDGFR and FGFR1 were highly expressed in SCCOHT tumors, suggesting that SCCOHTs are sensitive to ponatinib through the expression of these RTKs. Further, PDGFR-alpha phosphorylation and downstream signaling are strongly inhibited by ponatinib in SCCOHT. In summary we believe this finding may allow a way to be exploited therapeutically through the FDA-approved inhibitor ponatinib.

Citation Format: Jessica D. Lang, William Hendricks, Pilar Ramos, Holly Yin, Chris Sereduk, Jeffrey Kiefer, Yemin Wang, Anthony N. Karnezis, Bernard Weissman, David Huntsman, Jeffrey Trent. TARGETING AND EFFICACY OF THE RECEPTOR TYROSINE KINASE INHIBITOR PONATINIB IN SMALL CELL CARCINOMA OF THE OVARY, HYPERCALCEMIC TYPE, WORKS THROUGH INHIBITION OF PLATELET DERIVED GROWTH FACTOR RECEPTOR (PDGFR) [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-090.