Abstract LB-068: Inhibitors of Skp2 E3 ligase-mediated degradation of p27kip1 as a novel therapeutic approach to malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a highly aggressive cancer related to asbestos exposure for which there is no cure. Even with multimodal therapies median survival is only 24 months. Therefore, new therapeutic approaches are desperately needed for this cancer. MPMs are epithelioid, sarcomatoid, or composed of both patterns (biphasic); those tumors that are sarcomatous are most aggressive. Nuclear p27kip1 (p27) is a tumor suppressor critical to inhibiting cell proliferation by blocking Cdk2 activity to enforce cell cycle arrest. Cell cycle dysregulation has been shown to be involved in the pathogenesis of MPM. Accordingly, among the prognostic markers described for MPM, nuclear expression of p27 has been associated with increased progression-free survival. The levels of nuclear p27 are regulated post-translationally by the ubiquitin E3 ligase complex SCF-Skp2/Cks1, which causes its destruction. Accordingly, in many human cancers, Skp/Cks1 levels are high and associated with poor survival. Recently, we have shown that inhibitors of Skp2 E3 ligase activity block both, estrogen-induced degradation of nuclear p27 and inhibit proliferation of primary endometrial carcinoma cells in vitro as well as increase nuclear p27 and inhibit endometrial hyperplasia in vivo in estrogen-primed mice. Whereas nuclear p27 appears to be a good prognostic biomarker for MPM, the mechanistic relationship to high levels of Skp2 has not been shown. Hence, the aim of our study is to determine whether MPM is a candidate cancer for targeted Skp2 inhibitor therapy to regain cell cycle control. By gene expression profiling of 53 surgically resected MPM tumors and matched control tissue, Skp2 gene expression was elevated by 3-fold. In addition, by immunoblot analysis, we show that high levels of Skp2 protein are inversely related to p27 in four cell lines derived from MPM tumors of different tumor types. Interestingly, Skp2 expression was higher and associated with a higher proliferative rate in H2452 and HP-1 cells derived from biphasic tumors compared to those from epithelioid (H2591) or sarcomatoid (H2373) tumors and LP9 cells derived from normal pleural tissue expressed the lowest level of Skp2 and a lower proliferative rate. Similarly, by IHC of MPM tissue, Skp2 levels were inversely correlated with p27. These results suggest that Skp2 inhibitor therapy to stabilize nuclear p27 and regain growth control is a promising new approach for treatment of MPM. Citation Format: Julien Daubriac, Jonathan Melamed, Unnati Pandya, Harvey I. Pass, Leslie I. Gold. Inhibitors of Skp2 E3 ligase-mediated degradation of p27kip1 as a novel therapeutic approach to malignant pleural mesothelioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-068. doi:10.1158/1538-7445.AM2015-LB-068