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.
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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 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 > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1557139 |
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