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 3

Expression of the small T antigen confers resistance to SMAPs.

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Expression of the small T antigen confers resistance to SMAPs. (A and B)...
(A and B) 1 × 107 H358 control (A) and H358 small T antigen (ST) (B) cells were subcutaneously injected into nude mice and allowed to grow to an average of 100 mm3. Mice were treated with vehicle control (n = 9 for H358 control; n = 8 for H358 ST), a combination of 6 mg/kg MK2206 and 24 mg/kg AZD6244 (n = 8 for H358 control; n = 7 for H358 ST), and 5 mg/kg SMAP (n = 9 for H358 control; n = 7 for H358 ST) twice a day for 4 weeks. Tumor volume over course of treatment. (C) Representative TUNEL staining of treated tumors and immunohistochemistry of SV40 T antigen and p-ERK in treated animals. Scale bars: 20 μM. Original magnification: ×40. (D) Quantification of TUNEL positivity. (E) Quantification of SV40 T antigen levels. (F) Quantification of p-ERK levels. Quantification of SV40 T antigen and p-ERK levels in the xenograft tumors was performed by immunoblotting and densitometry. TUNEL, anti-SV40 T, and ERK signaling in the tumors were evaluated by sacrificing the mice 2 hours after final treatment. Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, Student’s t test.