Abstract 4717: Small molecule modulation of PP2A selectively induces oncogenic cytotoxicity through chronic and irreversible integrated stress response

Abstract

Abstract High-grade serous cancer (HGSC) is the most lethal gynecological malignancy and accounts for approximately 70% of all ovarian carcinomas. Despite recent advancements in drug discovery and a deeper understanding of the genetic mechanisms that drive HGSC oncogenesis, the mortality rate has remained stagnant over the past three decades, with a 5-year survival rate below 30%. Due to the prevalence of homologous recombination defects (HRD) in over 50% of HGSC tumors, the clinical management of patients harboring these genetic vulnerabilities has vastly relied on PARP inhibitors (PARPi). Nonetheless, about 80% of these patients ultimately relapse with refractory resistant and more aggressive disease, having no effective therapeutic alternatives currently available. Therefore, there is an urgent need for novel targeted therapies to be tailored towards the treatment of HGSC. Recently, we unveiled that 95% of HGSC tumors present with a widespread loss-of-heterozygosity in genes essential to form the tumor suppressor Protein Phosphatase 2A (PP2A) heterotrimer, second only to TP53. These deleterious alterations have been established to inhibit PP2A function, preventing it from counteracting oncogenic signatures that drive tumorigenesis. Our studies revealed that a Small Molecule Activator of PP2A (SMAP) synergizes with PARPi to induce synthetic lethality in HGSC cells while displaying favorable tolerability profiles in normal tissues. Mechanistically, SMAP activates distinct translational responses and stress signatures depending on the cellular context, driving selective oncogenic cytotoxicity through a chronic and irreversible integrated stress response (ISR), independent of PERK activation. In malignant contexts, SMAP-mediated activation of PP2A specifically drives the dephosphorylation of TFE3 to transcriptionally activate ATF4 and CHOP. Consequently, as cancer cells are incapable of activating adaptive homeostatic recovery mechanisms in response to SMAP, chronic ISR is induced, ultimately leading to cell death. Conversely, non-transformed cells leverage their intrinsic ISR plasticity to adapt, thereby restoring basal functions that allow cell survival under SMAP-mediated stress conditions. Collectively, our data highlights a new role of PP2A in HGSC and further underscore SMAP's selective cytotoxicity in cancer cells, independent of oncogenic genetic vulnerabilities or HRD profiles, by leveraging ISR plasticity and intrinsic adaptive homeostatic mechanisms. Thus, this class of PP2A modulators holds tremendous promise for broader therapeutic applications across diverse patient populations and tumor histological subtypes beyond HGSC, while mitigating standard-of-care therapy-associated toxicity. Citation Format: Rita A. Avelar, Riya Gupta, Grace Carvette, Felipe da Veiga Leprevost, Jose Colina, Jessica Teitel, Goutham Narla, Analisa DiFeo. Small molecule modulation of PP2A selectively induces oncogenic cytotoxicity through chronic and irreversible integrated stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4717.