Activation of PP2A and Inhibition of mTOR Synergistically Reduce MYC Signaling and Decrease Tumor Growth in Pancreatic Ductal Adenocarcinoma
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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. Significance: These findings present a combinatorial strategy targeting serine/threonine protein phosphatase PP2A and mTOR in PDA, a cancer for which there are currently no targeted therapeutic options.
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“and supporting combination therapeutic strategies (5).”
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Selective PP2A enhancement through biased heterotrimer stabilization
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- 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., & Sears, R. C.
- Affiliations
- Oregon Health & Science University (US)
- Cancer Research UK Scotland Institute (GB)
- Oncotide Pharmaceuticals (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
- Case Western Reserve University (US)
- Corresponding author
- Sears, Rosalie C.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-01-01
- Volume
- 79
- Issue
- 1
- Pages
- 209-219
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6318036
- OpenAlex
- W2899353968
- Cited by
- 85
- References
- 10
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 11 · 2023: 15 · 2022: 9 · 2021: 12 · 2020: 11 · 2019: 13
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (1F32CA192769-01, CA196228, CA100855, CA186241, CA209988, CA69533)
- U.S. Department of Defense (DOD) (BC061306)
- Susan G. Komen for the Cure (Susan G. Komen) (BCTR0706821)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- pancreatic ductal adenocarcinoma, protein phosphatase 2A, mTOR inhibition, c-Myc, Akt/mTOR signaling, phosphatase activation, apoptosis, treatment resistance, combination therapy
- MeSH terms
- Adenine, Animals, Benzoxazoles, Drug Synergism, Enzyme Activation, Humans, Pancreatic Neoplasms, Pyrimidines, Tumor Cells, Cultured, Proto-Oncogene Proteins c-myc, Apoptosis, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Proto-Oncogene Proteins c-akt, Mice, Protein Phosphatase 2, Small Molecule Libraries, TOR Serine-Threonine Kinases
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