Small-Molecule–Mediated Stabilization of PP2A Modulates the Homologous Recombination Pathway and Potentiates DNA Damage-Induced Cell Death

Abstract

High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, ~30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and an increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for cellular transformation (B56,B56 and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlate with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the homologous recombination (HR) output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and HR-deficient cells and in PDX models. Our studies identifies PP2A as a novel regulator of HR and indicates PP2A modulators as a therapeutic therapy for HGSC. In sum, our findings further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 presents benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.

TIPRL1 and its ATM-dependent phosphorylation promote radiotherapy resistance in head and neck cancer

“…Catalytic inhibition of PP2A-like phosphatases by LB-100, as well as loss of specific PP2A B-type subunits, Aα subunit or activator PTPA, have all been shown to inhibit HR and sensitize cells for DSBs (Ambjørn et al, 2021; Aouida et al, 2019; Kalev et al, 2012; Wei et al, 2013). As our data also suggested decreased repair and radiosensitization upon TIPRL1 depletion, this does again not seem to align well with a phosphatase inhibitory role of TIPRL1, although a recent publication demonstrated sensitization to PARP inhibitors by PP2A activating compounds (SMAPs) via a decrease in HR that was found dependent on RAD51 dysregulation (Avelar et al, 2023). Finally, the contribution of TIPRL1 to DSB repair may also involve its modulation of PP4 (Feng et al, 2016; Gingras et al, 2005), which has been shown to dephosphorylate a large number of DDR regulators (e.g.…”

PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis

“…Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is known to regulate key cellular functions such as cell growth, metabolism, and apoptosis (19). We recently identified a small-molecule activator of PP2A (SMAP) (20,21), and we and others demonstrated that PP2A reactivation is a therapeutically viable strategy in various cancer models (22)(23)(24)(25)(26)(27)(28)(29). Similar findings have been reported by modulating endogenous PP2A inhibitors such as CIP2A or SET (30).…”

“…We recently published on a series of first-in-class SMAPs (20,21). We and others previously reported that PP2A activation is a viable therapeutic strategy against cancer (22)(23)(24)(25)(26)(27)(28)(29). In one of the protein Bim to Mcl-1, Bcl-xL, and Bcl-2 following incubation with BH domain antagonists (VEN, S63845, or A1155463) in agonist mixtreated primary CLL cells that exhibited overexpression of antiapoptotic proteins and multidrug resistance.…”

MiR-181a targets STING to drive PARP inhibitor resistance in BRCA- mutated triple-negative breast cancer and ovarian cancer

“…To assess whether this association was also observed with PARPi, two isogenic OvCa cell line pairs (OV81.2 and OV231) were analyzed. The two OvCa cell line pairs were generated through platinum-drug selection and became cisplatin and PARPi resistant [ 25 , 26 ]. We found that the miR-181a levels were significantly increased in cisplatin- and PARPi-resistance cell lines compared to corresponding parental cell lines (Fig.…”