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

The Journal of Clinical Investigation
Jaya SangodkarGoutham Narla

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.

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Citations

Dec 21, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Henan ZhaoXiaohong Shu
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Methods Mentioned

BETA
xenograft
transgenic
footprinting
xenografts
electrophoresis
PCR
equilibrium dialysis

Software Mentioned

Schrödinger package
ImageJ
Protein Preparation Wizard
Mass Matrix
LigPrep
PyMol

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