Abstract 3975: Pharmacologic inhibition of the ΔNp63/DGCR8 axis as a novel therapeutic strategy for p53-deficient and mutant tumors

The p63 gene is a member of the p53 family, whose transcription is driven by two alternative promoters, allowing the expression of two distinct isoforms: TAp63 and ΔNp63. In order to determine their roles in tumorigenesis, our group has generated isoform-specific knockout mouse models. TAp63 was found to be a pivotal tumor and metastasis suppressor, whose function is achieved by the regulation of the miRNA biogenesis pathway in a Dicer dependent way. ΔNp63 was shown to be a master regulator of the differentiation of epithelial tissues, such as the epidermis. Np63 is indeed able to directly induce the expression of DGCR8, a co-factor essential in modulating miRNA biogenesis, sustaining in this manner a proper epidermal differentiation. Accordingly, ΔNp63 knockout mice die shortly after birth because of developmental defects. In addition to characterize its role in skin development, our group has recently demonstrated that ΔNp63 may act as an oncogene by counteracting TAp63 tumor suppressive activities in vivo: specific deletion of ΔNp63 in p53−/− thymic lymphomas caused TAp63 reactivation and consequent tumor shrinkage. Based on all these findings, we hypothesized that ΔNp63 might support tumor formation not only by inhibiting TAp63, but also by affecting miRNA maturation in a DGCR8 dependent manner. In line with this hypothesis, we deem that the inhibition of the ΔNp63/DGCR8 axis might be crucial to curb ΔNp63 tumor promoting activities. To this end, we screened a drug library of more than 850 FDA approved compounds looking for inhibitors of the ΔNp63/DGCR8 axis. We found several small molecules that were able to reduce ΔNp63 protein stability and, as a result, to decrease the expression levels of its target gene DGCR8 and that of a specific set of miRNAs, whose biosynthesis is DGCR8-dependent. On the contrary, the levels of DGCR8-independent miRNAs were not affected by the drug treatments. In agreement with our hypothesis, curbing the ΔNp63/DGCR8 axis by either these drugs or inhibitors against the identified miRNAs, reduced cell viability of different cancer cell types of both murine and human origin, without affecting that of normal cells. In vivo analyses of these compounds as well as of these miRNA inhibitors have showed their efficacy in counteracting tumor formation and progression in mice. In summary, we believe that the in vitro and in vivo characterization of the ΔNp63/DGCR8 axis will provide a novel and effective strategy to target tumors relying on ΔNp63 for their expansion, especially the most therapeutically challenging ones devoid of a functional tumor suppressor p53. Citation Format: Marco Napoli, Avinashnarayan Venkatanarayan, Payal Raulji, Hussein A. Abbas, William Norton, Anil K. Sood, Gabriel Lopez-Berestein, Kenneth Y. Tsai, Cristian Coarfa, Preethi H. Gunaratne, Elsa R. Flores. Pharmacologic inhibition of the ΔNp63/DGCR8 axis as a novel therapeutic strategy for p53-deficient and mutant tumors. [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 3975. doi:10.1158/1538-7445.AM2015-3975