Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Jaya Sangodkar, … , Michael Ohlmeyer, Goutham Narla
Jaya Sangodkar, … , Michael Ohlmeyer, Goutham Narla
Published May 15, 2017
Citation Information: J Clin Invest. 2017;127(6):2081-2090. https://doi.org/10.1172/JCI89548.
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Concise Communication Genetics Oncology

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

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.

Authors

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

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Figure 5

Effects of mutations in putative drug-binding site.

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Effects of mutations in putative drug-binding site. (A) Male nude mice w...
(A) Male nude mice were subcutaneously injected (1 × 107 cells per injection) in the right flank with the different isogenic cell lines (control EGFP and putative drug-binding mutant K194R). Once the tumors reached a volume of 100 mm3, the mice were randomly enrolled in vehicle control (n = 6 for EGFP; n = 9 for K194R), a combination of 6 mg/kg MK2206 and 24 mg/kg AZD6244 (n = 8 for EGFP; n = 7 for K194R), or 5 mg/kg SMAP (n = 7 for EGFP; n = 9 for K194R) twice a day for 4 weeks. Mouse tumor volume for control EGFP-expressing H358 xenograft over course of treatment. (B) Tumors were evaluated by sacrificing the mice 2 hours after final treatment. Representative TUNEL staining and p-ERK IHC of treated tumors. Scale bars: 20 μM. Original magnification: ×40. (C) Quantification of TUNEL positivity in tumor. (D) Quantification of p-ERK levels in the xenograft tumors as performed by immunoblotting and densitometry. (E) Mouse tumor volume for drug-binding mutant K194R expressing H358 xenograft over course of treatment. Tumor volume over course of treatment. (F) Tumors were evaluated by sacrificing the mice 2 hours after final treatment. Representative TUNEL staining and p-ERK IHC of treated tumors. Scale bar: 20 μM. Original magnification: ×40. (G) Quantification of TUNEL positivity in tumors treated. (H) Quantification of p-ERK levels in xenograft tumors as performed by immunoblotting and densitometry. Data represent mean ± SEM. **P < 0.01; ***P < 0.001, Student’s t test.