Abstract 2981: Biased activation of PP2A through selective heterotrimer binding and stabilization
| Autor: | Stefan Schüchner, Derek J. Taylor, Abbey L. Perl, David L. Brautigan, Goutham Narla, Wenqing Xu, Zhizhi Wang, Daniela Schlatzer, Danica Wiredja, Daniel Leonard, Nikhil Vasireddi, Wei Huang, Caitlin M. O’Connor, Yinghua Chen, Janna Kiselar, Nilesh Zaware, Egon Ogris, Sudeh Izadmehr, Matthew D. Glasky |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cancer Research. 80:2981-2981 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Development of molecularly targeted therapies have shifted our clinical approach to cancer allowing for an integrated treatment approach where tumor genotype and molecular profiles are paired in a clinically actionable manner with specific targeted therapies. This approach maximizes efficacy and minimizes toxicity for each patient. While the vast majority of molecularly targeted therapies have focused on the development of kinase inhibition, an equally effective yet underexplored strategy exists in the activation or regulation of phosphatases. The tumor suppressor Protein Phosphatase 2A (PP2A) negatively regulates multiple oncogenic drivers common to a broad range of human malignancies including MYC, AKT, and ERK; and has been demonstrated as a critical tumor suppressor. In cancer, PP2A is inactivated through several mechanisms including increased expression of endogenous inhibitors, post-translational modifications of the catalytic subunit, and somatic mutation in its catalytic, regulatory or scaffold subunits. The vast mechanisms employed to dysregulate and inhibit PP2A in cancer, highlights it's potential as an endogenous molecular target to combat malignant growth. Our laboratory has been involved in the development of a novel series of small molecule activators of PP2A (SMAPs). Using structural, biochemical, cellular, and in vivo model systems we reveal how the lead SMAP, DT-061, specifically stabilizes a B56 containing PP2A holoenzyme, in its fully assembled, active state, to direct enzymatic activity towards specific oncogenic targets, including its well-known substrate c-MYC. Our structure identifies a unique interfacial small molecule binding pocket that involves all three PP2A subunits to prevent dissociation of select B56 subunit containing holoenzymes. Elucidating the mechanism of SMAPs allowed us to explore appropriate clinical placement for this targeting strategy and investigate potential mechanisms of resistance. For example, in vivo xenograft studies of cancer-associated Aα mutants, most notably R183W, demonstrates that these mutations render malignant cells resistant to these SMAPs and further support the mechanism of SMAPs described. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets. Citation Format: Daniel Leonard, Wei Huang, Sudeh Izadmehr, Caitlin M. O'Connor, Danica D. Wiredja, Zhizhi Wang, Nilesh Zaware, Daniela M. Schlatzer, Stefan Schuchner, Janna Kiselar, Yinghua Chen, Nikhil Vasireddi, Abbey L. Perl, Matthew D. Glasky, Wenqing Xu, David L. Brautigan, Egon Ogris, Derek J. Taylor, Goutham Narla. Biased activation of PP2A through selective heterotrimer binding and stabilization [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2981. |
| Databáze: | OpenAIRE |
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