Understanding Tumor Suppressive Functions of Protein Phosphatase 2A

Colorectal Cancer (CRC) is the third most common cancer in men and women. While the 5-year survival rate for localized CRC is 91%, the survival rate is less than 14% for patients with disseminated disease. With few exceptions, metastatic CRC is incurable, largely due to resistance to available therapies. As a result, CRC is the second leading cause of cancer death in the U.S.A. These statistics highlight an urgent clinical need for develop- ment of effective treatments for patients with advanced CRC. Aberrant cap-dependent mRNA translation initia- tion (CDT) has emerged as an attractive target for the clinical management of CRC based on its key role in supporting selective synthesis of crucial oncogenic drivers such as growth factors, cell cycle regulators, anti- apoptotic proteins, and Myc. A key negative regulator of CDT is 4E-BP1 which blocks the formation of the translation initiation complex, eIF4F, by stochiometric binding to eIF4E. 4E-BP1 acts as a nexus for aberrant upregulation of CDT by oncogenic signaling pathways that drive CRC (e.g., Wnt/β-catenin, RAS/RAF/ERK, PI3K/AKT/mTOR). These pathways inactivate 4E-BP1 by (a) inhibitory phosphorylation, and/or (b) reducing the 4E-BP1:eIF4E ratio through upregulation of eIF4E or downregulation of 4E-BP1. Inactivation of 4E-BP1 is not only critical for the transformed phenotype but is also a major mechanism underlying failure of targeted therapeutics, including inhibitors of mTOR and the ERK pathway, which rely on inhibition of CDT for their antitumor effects. Thus, restoration of 4E-BP1 holds promise for sensitization of CRCs to a broad range of targeted agents. This proposal builds on our finding that a subset of protein phosphatase 2A (PP2A) heterotri- mers are potent regulators of 4E-BP1 and CDT. Our group has developed first-in-class Small Molecule Activators of PP2A (SMAPs) that activate a subset of B56-PP2As for tumor suppression in CRC and other cancer types. A lead SMAP (EV440/SW-3431) is in clinical development by Springworks Therapeutics, with phase 1 clinical trials anticipated in early 2026. We have discovered that SMAPs orchestrate a PP2A-dependent translation repressive program in CRC cells by (a) activating 4E-BP1 through hypophosphorylation, and (b) upregulating 4E-BP1 levels, even in tumors that lack 4E-BP1 expression. These findings support activation of specific PP2A(s) as a powerful strategy for restoration of translation control in CRCs. We hypothesize that 4E-BP1 translation repressive function can be restored in CRC cells by activation of specific B56-PP2A phosphatase(s) for inhibition of translationally regulated oncogenic drivers, tumor suppression, and sensitization to targeted therapies. Three Aims are proposed: (1) Define the B56-PP2A→4E-BP1 signaling axis in colorectal cancer, (2) Explore 4E-BP1- dependent antitumor effects of B56-PP2A activation in colorectal cancer cells, and (3) Determine the potential of PP2A-mediated restoration of 4E-BP1 function for colorectal cancer therapy. Proposed studies will define mechanisms of translation control in CRCs and explore a novel antitumor strategy, i.e., PP2A-mediated restora- tion of active 4E-BP1, for managing advanced CRC in patients. Project Number: 1R01CA300564-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jennifer Black (+1 co-PI) | Institution: UNIVERSITY OF NEBRASKA MEDICAL CENTER, OMAHA, NE | Award Amount: $651,038 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics A Study Section[MCTA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298549