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

Target c-Myc to treat pancreatic cancer

“…revealed that the use of small-molecule activators of PP2A (SMAPs) in different cancers such as Burkitt lymphoma, KRAS-driven non–small cell lung cancer, and triple-negative breast cancer has been associated with decreased c-Myc bioavailability and diminished tumor cells proliferation. 168 Similarly, B56α subunit knockdown has been associated with deregulated c-Myc activity and spontaneous tumor development in the liver of mice. 169 Endogenous inhibitors of PP2A and cancerous inhibitors of PP2A are markedly overexpressed in pancreatic cancer and enhance the expression and stabilization of c-Myc in human pancreatic cancer.…”

PPP2R4 dysfunction promotes KRAS-mutant lung adenocarcinoma development and mediates opposite responses to MEK and mTOR inhibition

“…MYC overexpression is a well-known mediator of therapy resistance (30), and recent publications have identified PP2A dysfunction as a new partner in crime (28,29). We have now identified kinase inhibitors of which the efficiency is influenced by decreased PTPA expression in KRAS-mutant cells.…”

“…PP2A dysfunction has recently been implicated in therapeutic resistance of endometrial and lung cancer cells to kinase inhibition (28,29). Together with the PTPA loss-associated increase of c-MYC expression, another mediator of cancer therapy resistance (30), this prompted us to assess the role of PTPA depletion on the therapeutic outcome of a range of kinase inhibitor therapies. We assembled a confined library of 18 kinase inhibitors, of which their targets are regulated by and/or regulate activity of either PP2A or c-MYC (Supp.…”

“…Importantly, PP2A inactivation was recently found to induce therapy resistance against a wide range of targeted anti-cancer compounds, including MEK inhibition (28,29). Moreover, direct pharmacological activators of PP2A were identified as novel classes of promising anticancer drugs in a broad range of cancers (28)(29)(30)(31)(32)(33)(34)(35), including KRAS-mutant NSCLC (29). A common denominator in several of these studies seemed to be the involvement of the oncogenic transcription factor c-MYC (30), of which the stability is closely regulated by a specific subset of PP2A holoenzymes (36)(37)(38).…”

Strategies for Targeting Serine/Threonine Protein Phosphatases with Small Molecules in Cancer

“…In contrast to iHAP1, which activates the B56ε-containing PP2A and dephosphorylates MYBL2, SMAPs activate the B56α-containing PP2A, induce the dephosphorylation of c-MYC and ERK, and arrest the cell cycle in G0/G1 phase (Figure A). Thus, SMAPs show antitumor activities against MYC-driven cancers (T-ALL, Burkitt lymphoma, KRAS-driven nonsmall-cell lung cancer, and triple-negative breast cancer) and EGFR-driven cancer (lung adenocarcinoma). ,, Importantly, a cocrystal structure (PDB code: 6NTS) of the PP2A-DT-061 complex was solved at 3.6 Å in 2020 by single-particle cryo-electron microscopy (cryo-EM). As shown in Figure B, DT-061 works as a “molecular glue” that is located in a pocket formed by the intersection interface of three PP2A subunits (including the scaffold Aα subunit (A subunit), catalytic Cα subunit (C subunit), and B56α regulatory subunit (B subunit)) and forms multiple types of interactions with all three subunits to stabilize the PP2A heterotrimers.…”