Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers

Abstract

The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. One of the best-characterized PP2A substrates is MYC proto-oncogene basic helix–loop–helix transcription factor (MYC), whose overexpression is commonly associated with aggressive forms of this disease. PP2A directly dephosphorylates MYC, resulting in its degradation. To explore the therapeutic potential of direct PP2A activation in a diverse set of MYC-driven cancers, here we used biochemical assays, recombinant cell lines, gene expression analyses, and immunohistochemistry to evaluate a series of first-in-class small-molecule activators of PP2A (SMAPs) in Burkitt lymphoma, KRAS-driven non–small cell lung cancer, and triple-negative breast cancer. In all tested models of MYC-driven cancer, the SMAP treatment rapidly and persistently inhibited MYC expression through proteasome-mediated degradation, inhibition of MYC transcriptional activity, decreased cancer cell proliferation, and tumor growth inhibition. Importantly, we generated a series of cell lines expressing PP2A-dependent phosphodegron variants of MYC and demonstrated that the antitumorigenic activity of SMAPs depends on MYC degradation. Collectively, the findings presented here indicate a pharmacologically tractable approach to drive MYC degradation by using SMAPs for the management of a broad range of MYC-driven cancers.

CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis

“…6C). Similar to other in vivo studies with SMAPs 15,47,49,50 , we did not observe any treatment-related adverse effects in mice. Importantly the control tumors were CIP2A positive whereas tumors from DT-061 treated mice showed a clear trend for reduced CIP2A protein levels (Fig.…”

“…However, it is important to note that we consider SMAPs as surrogate CIP2A inhibitors that also have acute effects not mediated by CIP2A inhibition 15 , thereby explaining the effects of SMAPs also in other types of cancer cells 47,49,50 . Importantly, we validated the Together these results credential a therapeutically actionable driver protein for one of the most aggressive human cancer types, BLBCs.…”

Perphenazine exerts antitumor effects on HUT78 cells through Akt dephosphorylation by protein phosphatase 2A

“…As for the HUT78 cells, Akt inhibitor is enough to kill cells and PP2A activator may be not necessary to use. PP2A activators suppress multiple signals not only Akt but also such as c-myc and E2F ( 31 , 32 ). Therefore, the effect of the PP2A activator is not limited to Akt inhibition, and the usage of Akt inhibitors and PP2A activators may be different from drug-resistant point of view.…”

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

“…PP2A-activating drugs are known to be highly effective in reducing MYC activity in several types of cancers [135][136][137]. Notably, small molecules that prevent SET-PP2A interaction such as FTY720, OP449, and CM-1231 re-activates PP2A, inhibiting cell proliferation and promoting apoptosis in AML and CML cell lines and primary patient samples [62,63,68,83,92,106,108,[138][139][140].…”