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

Sangodkar, J; Perl, A; Tohme, R; Kiselar, J; Kastrinsky, DB; Zaware, N; Izadmehr, S; ... Narla, G; + view all (2017) Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. Journal of Clinical Investigation , 127 (6) pp. 2081-2090. 10.1172/JCI89548. Green open access

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Abstract

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.

Type: Article
Title: Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI89548
Publisher version: http://dx.doi.org/10.1172/JCI89548
Language: English
Additional information: This is the published version of record. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > SoP Pharmaceutical and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1557139
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