Activation of PP2A and Inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma

Allen-Petersen, B. L. et al. (2019) Activation of PP2A and Inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma. Cancer Research, 79(1), pp. 209-219. (doi: 10.1158/0008-5472.CAN-18-0717) (PMID:30389701) (PMCID:PMC6318036)

Abstract

In cancer, kinases are often activated and phosphatases suppressed, leading to aberrant activation of signaling pathways driving cellular proliferation, survival, and therapeutic resistance. Although pancreatic ductal adenocarcinoma (PDA) has historically been refractory to kinase inhibition, therapeutic activation of phosphatases is emerging as a promising strategy to restore balance to these hyperactive signaling cascades. In this study, we hypothesized that phosphatase activation combined with kinase inhibition could deplete oncogenic survival signals to reduce tumor growth. We screened PDA cell lines for kinase inhibitors that could synergize with activation of protein phosphatase 2A (PP2A), a tumor suppressor phosphatase, and determined that activation of PP2A and inhibition of mTOR synergistically increase apoptosis and reduce oncogenic phenotypes in vitro and in vivo. This combination treatment resulted in suppression of AKT/mTOR signaling coupled with reduced expression of c-MYC, an oncoprotein implicated in tumor progression and therapeutic resistance. Forced expression of c-MYC or loss of PP2A B56α, the specific PP2A subunit shown to negatively regulate c-MYC, increased resistance to mTOR inhibition. Conversely, decreased c-MYC expression increased the sensitivity of PDA cells to mTOR inhibition. Together, these studies demonstrate that combined targeting of PP2A and mTOR suppresses proliferative signaling and induces cell death and implicates this combination as a promising therapeutic strategy for patients with PDA.

• Item Type: Articles
• Additional Information: B.L. Allen-Petersen was supported by Tartar Research Fellowship Award and F32 CA192769. R.C. Sears was supported by R01 CA100855, CA186241, CA196228, U54 CA209988, DOD BC061306; Komen BCTR0706821, and the Brenden-Colson Foundation. Histopathology and Flow Cytometry Core services were supported by the OHSU Knight Cancer Institute Cancer Center Support Grant P30 CA69533.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morton, Professor Jen and Sansom, Professor Owen
• Authors: Allen-Petersen, B. L., Risom, T., Feng, Z., Wang, Z., Jenny, Z. P., Thoma, M. C., Pelz, K. R., Morton, J. P., Sansom, O. J., Lopez, C. D., Sheppard, B., Christensen, D. J., Ohlmeyer, M., Narla, G., and Sears, R. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 0008-5472
• ISSN (Online): 1538-7445
• Published Online: 02 November 2018
• Copyright Holders: Copyright © 2018 American Association for Cancer Research
• First Published: First published in Cancer Research 79(1):209-219
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher