Abstract 2562: eIF4E modulators to address breast cancer resistance

Abstract

Abstract ER+/HER2- advanced or metastatic breast cancers represents a large patient population served by CDK4/6 inhibitors combined with hormonal therapy as standard of care. As acquired resistance emerges, molecular profiling indicates about > 100 different mutations render resistance, creating challenges for treating physicians, patients, and the healthcare system broadly. The aim of our work is to maintain consolidation of this large patient population by developing targeted therapies to a key fundamental mechanism at the convergence of many oncogenic signaling pathways through which resistance arises. The regulation of CAP dependent protein translation is a central element in oncogenesis. One of a family of CAP binding proteins, eIF4E serves to anchor the m7GTP CAP of RNA into several protein complexes and regulates multiple aspects of mRNA processing such as nuclear export and ribosomal translation. Our efforts focused on simultaneously developing potent small molecule modulators of eIF4E and patient hypotheses through which to direct their initial clinical use. By aligning medicinal chemistry tools with patient directed pharmacology, we optimized our inhibitors to identify orally bioavailable, nM modulators of eIF4E. Biochemical assays demonstrated direct binding and allosteric modulation of eIF4E activity by PICRN941, along with Proximity Ligation Assays (PLA) demonstrating reduced eIF4E and 4G association in cells. Western analysis demonstrated that PICRN941 induced simultaneous and significant modulation of a number of key oncogenes that have been postulated to drive intrinsic or acquired resistance in response to standard of care including anti-estrogen treatment, CDK4/6 inhibitors or PI3K inhibitors combined with hormonal therapy, including MYC, CDK2, CDK4, CCND1 and eIF4E itself. Treatment of ER+ breast cancer cell lines including ZR-75-1, T47D, and ZR-75-30 with PICRN941 induced a dose dependent reduction in the levels of hyper-phosphorylated 4E-BP1 commensurate to increases in unphosphorylated 4E-BP1, and dose-dependent reduction in protein expression of Cyclin D1, CDK4, ER alpha, phosphorylated Rb and eIF4E. Reduced protein expression correlated with subsequent cell cycle arrest and apoptosis. We further studied our inhibitors in primary patient derived organoids in collaboration with the Hubrecht Institute, where we observed potent and complete responses in breast cancer organoids that represent patient populations where unmet needs remain high including PTEN and RB null organoid models. Markers of target engagement correlated well with organoid model sensitivity, including Cyclin D1 responses. Our findings suggest that our allosteric eIF4E modulators may provide a unique and efficient therapeutic approach to address multiple resistance mechanisms across cancer patient populations, toward fulfilling the promise of this elusive target. Citation Format: Lisa Sturla, Bassil Dekky, Xuemei Zhang, Katherine S. Bowdish, Chris VanDeusen. eIF4E modulators to address breast cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2562.