Abstract 3325: PELO is a synthetic lethal target in FOCAD deleted cancers

Abstract During protein translation, ribosomes may stall for a number of reasons including the presence of mRNA defects, cell stress, nonoptimal codon clusters, ribosome collisions, etc. One mechanism of resolving these stalled ribosomes is to extract the mRNA using the SKI complex. Focadhesin (FOCAD) provides an essential function to the SKI complex by stabilizing and protecting SKI proteins from degradation, but it is also a common collateral deletion with CDKN2A- and MTAP-loss in many cancers. In the absence of a functional SKI complex, stalled ribosomes are resolved via the No-go decay (NGD) pathway which leverages PELO (protein pelota homolog), HBS1L (HBS1-like protein), and ABCE1 (ATP-binding cassette sub-family E member 1) . Together PELO and HBS1L recognize stalled ribosomes and recruit ABCE1 to split and recycle ribosomal subunits. Consistent with the NGD pathway compensating for the loss of a functional SKI complex in normal cells, unbiased whole-genome knockout screens identify FOCAD-deleted cell lines to be dependent on PELO for their survival. In this work, PELO-dependency is validated in FOCAD-deleted cancer cell lines and it is demonstrated that FOCAD-deletion drives PELO-dependency. Furthermore, it is shown that PELO-knockout induces ribosomal readthrough, GCN2 activation, and EIF2α induction in FOCAD-deleted cell lines prior to the robust anti-proliferative and apoptotic readouts observed at longer timepoints. Together, these data support that loss of PELO in FOCAD-deleted cancer cells is synthetic lethal due to the persistence of stalled ribosomes that initially activate cell survival pathways but ultimately lead to cell death. Citation Format: Michelle Patricia Cicchini, Yang Peng, Yanhua Rao, Biju Mangatt, Benjamin Schwartz. PELO is a synthetic lethal target in FOCAD deleted cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3325.