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Ref Type Journal Article
PMID (28504649)
Authors Sangodkar J, Perl A, Tohme R, Kiselar J, Kastrinsky DB, Zaware N, Izadmehr S, Mazhar S, Wiredja DD, O'Connor CM, Hoon D, Dhawan NS, Schlatzer D, Yao S, Leonard D, Borczuk AC, Gokulrangan G, Wang L, Svenson E, Farrington CC, Yuan E, Avelar RA, Stachnik A, Smith B, Gidwani V, Giannini HM, McQuaid D, McClinch K, Wang Z, Levine AC, Sears RC, Chen EY, Duan Q, Datt M, Haider S, Ma'ayan A, DiFeo A, Sharma N, Galsky MD, Brautigan DL, Ioannou YA, Xu W, Chance MR, Ohlmeyer M, Narla G
Title Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth.
Journal Vol Issue Date Pages Journal Short Title
The Journal of clinical investigation 127 6 2017 Jun 01 2081-2090 J Clin Invest
URL
Abstract Text Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
DT-061 DT-061 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
DT-061 SMAP PP2A Activator 7 DT-061 is a small molecule that activates PP2A which results in growth inhibition and apoptosis in tumor cells (PMID: 28504649, PMID: 30021885).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References