Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Sangodkar, Jaya; Perl, Abbey; Tohmé, Rita; Kiselar, Janna; Kastrinsky, David B.; Zaware, Nilesh; Izadmehr, Sudeh; Mazhar, Sahar; Wiredja, Danica; O’Connor, Caitlin M.; Hoon, Divya; Dhawan, Neil; Schlatzer, Daniela; Shen, Yao; Léonard, Daniel; Borczuk, Alain C.; Gokulrangan, Giridharan; Wang, Lifu; Svenson, Elena; Farrington, Caroline; Yuan, Eric; Avelar, Rita A.; Stachnik, Agnes; Smith, Blake E.; Gidwani, Vickram; Giannini, H.M.; McQuaid, Daniel; McClinch, Kimberly; Wang, Zhizhi; Levine, Alice C.; Sears, Rosalie C.; Chen, Edward Y.; Duan, Qiaonan; Datt, Manish; Haider, Shozeb; Ma’ayan, Avi; DiFeo, Analisa; Sharma, Neelesh; Galsky, Matthew D.; Brautigan, David L.; Ioannou, Yiannis A.; Xu, Wenqing; Chance, Mark R.; Ohlmeyer, Michael; Narla, Goutham

doi:10.1172/jci89548

Cited by 168 publications

(252 citation statements)

References 49 publications

Supporting

Mentioning

230

Contrasting

Order By: Relevance

“…In accordance with the major theme of this review, a recent study demonstrated that combination of SET targeting and tyrosine kinase inhibitor provides an effective therapeutic approach in human T-cell acute lymphoblastic leukemia [34]. Apart of small-molecules targeting the PIPs, the novel series of orally bioavailable and nontoxic PP2A reactivator molecules with profound in vivo therapeutic activities in KRAS mutant lung cancers and castration-resistant prostate cancer [47,48], provide a very encouraging example that PP2A indeed is druggable [14,39]. In the context of this review, these small-molecule PP2A activators were recently shown to transform the cytostatic MEK inhibitor responses to cytotoxic, and to greatly promote in vivo therapeutic effects of MEK inhibitor AZD6244 in two KRAS mutant lung cancer xenograft models [15].…”

Section: Therapeutic Targeting Of Pp2amentioning

confidence: 64%

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Westermarck

2018

The FEBS Journal

View full text Add to dashboard Cite

Therapies targeting tyrosine and serine/threonine kinases have raised enormous interest as potential cure for cancer patients in many common cancer types. However, except for the success story with BCR/ABL tyrosine kinase inhibitors in chronic myeloid leukemia (CML), critical review of results of a large number of clinical trials indicates that the clinical success with kinase inhibitors has been overall disappointing. These alarming results call for critical assessment of whether there is some fundamental flaw in the design of strategies to target phosphorylation-dependent oncogenic signaling for cancer therapy. This viewpoint debates on one potential, but thus far largely neglected, molecular explanation why inhibition of protein kinases is not sufficient for cancer cure. We note that the phosphorylation status, and thus the oncogenic potential of any given protein, is not regulated only by kinases, but rather by an intimate balance between kinases and their antagonist phosphatases. We further review the supporting functional evidence that for oncogenic transformation of human cells it is not enough to activate kinase signaling by activated kinases, if a group of counteracting tumor suppressor phosphatases is not inactivated. Based on these considerations, and a very recently emerged role of oncogenic function of a group of phosphatase inhibitor proteins as human oncoproteins, we propose that in order to efficiently inhibit phosphorylation-dependent signaling in cancer cells, and thus provide better therapeutic index, the kinase inhibitors should be combined with strategies to reactivate tumor suppressor phosphatases such as Protein Phosphatase 2A (PP2A).

show abstract

Section: Therapeutic Targeting Of Pp2amentioning

confidence: 64%

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Westermarck

2018

The FEBS Journal

View full text Add to dashboard Cite

show abstract

“…1A) would compromise BBB permeability, and eventually CNS availability, of the SMAPs as compared to tricyclics. We therefore started by investigating the in vitro BBB passage of NZ-8-061 (a.k.a DT-061) that has been widely used in cancers outside the CNS (Sangodkar et al, 2017;McClinch et al, 2018). Quantified by HPLC-MS/MS, NZ-8-061 was found to cross the artificial BBB (Le Joncour et al, 2019), consisting of murine brain microcapillary endothelial cells and astrocytes ( Fig.…”

Section: Development Of Blood-brain Barrier Permeable Small Molecule mentioning

confidence: 99%

“…As a pharmacologic control, U87MG, U118, or A172 cells were also treated with increasing doses of TRC-766, a structurally similar but biologically inactive derivate of SMAPs ( Supplementary Fig. 3A) (Sangodkar et al, 2017;McClinch et al, 2018).…”

Section: Nz-8-061 Potently Inhibits the Viability Of Gb Cells With Hementioning

confidence: 99%

“…A series of small molecule activators of PP2A (SMAPs), was recently derived from tricyclic neurological drugs such as Chlorpromazine and Clomipramine (Kastrinsky et al, 2015). Based on photoaffinity labeling studies, radiolytic footprinting, and mutagenesis of the binding site, the target of SMAPs has been identified as the interface of the A and C subunits in the PP2A complex (Sangodkar et al, 2017). The SMAPs have shown efficacy as orally available monotherapy in animal models in solid non-CNS cancer types (Sangodkar et al, 2017;, but neither their BBB penetration properties, nor potential as CNS cancer drug has not been studied as yet.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

Merisaari

Denisova

Doroszko

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GB) is a fatal disease in which most targeted therapies have clinically failed.However, pharmacological reactivation of tumor suppressors has not been thoroughly studied as yet as a GB therapeutic strategy. Tumor suppressor Protein Phosphatase 2A (PP2A), is inhibited by non-genetic mechanisms in GB, and thus it would be potentially amendable for therapeutic reactivation. Here we demonstrate, that small molecule activators of PP2A (SMAPs), NZ-8-061and DBK-1154, effectively cross the in vitro model of blood-brain barrier (BBB), and in vivo partition to mouse brain tissue after oral dosing. In vitro, SMAPs exhibit robust cell killing activity against five established GB cell lines, and nine patient-derived primary glioma cell lines.Collectively these cell lines have heterogenous genetic background, kinase inhibitor resistance profile, and stemness properties; and they represent different clinical GB subtypes. Oral dosing of either of the SMAPs significantly reduced growth of infiltrative intracranial GB tumors. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested GB cell lines, also significantly increased survival of mice bearing orthotopic GB xenografts. In summary, this report presents a proof-of-principle data for BBB-permeable tumor suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background.

show abstract

“…Subsequent reengineering of these compounds eliminated their CNS effects while retaining and/or even enhancing their anticancer activity. In this issue, Sangodkar et al (15) now show that these reengineered compounds, termed small molecule activators of PP2A (SMAPs), share the ability to activate PP2A. Biochemical studies identified the PP2A A subunit as the primary target of SMAPs, specifically the centrally located HEAT repeats five to eight.…”

Section: Smaps: New Kids In Townmentioning

confidence: 99%

A SMAP in the face for cancer

Shenolikar¹

2017

Journal of Clinical Investigation

View full text Add to dashboard Cite

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

Cited by 168 publications

References 49 publications

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Targeted therapies don't work for a reason; the neglected tumor suppressor phosphatase PP2A strikes back

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

A SMAP in the face for cancer

Contact Info

Product

Resources

About