Abstract 4343: A focused CRISPR screen to identify synthetic lethal interactions with the novel eIF4A inhibitor eFT226 in KRAS driven NSCLC
Authors: Young Nathan P. , Stumpf Craig R. , Chen Joan , Chiang Gary G. , Thompson Peggy A. , Webster Kevin R. 
Published: August 2019

Tumor development is often characterized by dysregulated messenger RNA (mRNA) translation of key oncogenic factors that promote increased proliferation, resistance to apoptosis and enhanced metastatic potential. The eukaryotic translation initiation factor 4F (eIF4F) complex, a master regulator of protein synthesis, is comprised of eIF4E (mRNA-cap-binding protein), eIF4A (RNA-helicase), and eIF4G (scaffolding protein), that together orchestrate mRNA recruitment to ribosomal subunits as well as efficient scanning of the mRNA 5’-untranslated region. As a downstream target of growth-promoting signaling cascades, eIF4F also serves as a central node in several important oncogenic pathways including KRAS and PI3K/mTOR. eIF4F subunits are frequently over-expressed in various malignancies; therefore, repressing eIF4F activity has emerged as a promising anti-cancer therapeutic strategy. eFT226 is a potent and selective translational regulator that targets eIF4A1. eFT226 down-regulates the translation of a unique gene set and displays robust anti-tumor activity across multiple models in vitro and in vivo. A functional genomic screen using CRISPR/Cas9 was performed to discover synthetic lethal genetic interactions with eFT226 to enable development of novel drug combination and/or patient selection strategies. The screen was conducted in a panel of non-small cell lung cancer (NSCLC) cell lines driven by oncogenic KRAS and p53 pathway mutations, a tumor subtype with limited therapeutic options. Utilizing a focused guide RNA (gRNA) lentiviral library of ~700 cancer-related targets with diverse roles in growth-factor signaling, metabolism, epigenetics, translation and stress-responses, several genetic perturbations that sensitized tumor cells to eFT226 were uncovered. Interestingly, many of the genes whose loss-of-function enhanced eFT226’s activity fall into distinct classes including an oncogenic signaling pathway commonly activated in many cancers as well as redox homeostasis. Moreover, a number of these targets include tumor suppressor genes that are frequently mutated or inactivated through loss of function in certain cancer types suggesting that specific genetic contexts may dictate eFT226 efficacy. Ongoing studies are aimed at confirming these hits from the primary screen. Collectively, these validated targets will represent genomic vulnerabilities to eFT226 that can aid in the design of drug combination and patient selection strategies for NSCLC.

Citation Format: Nathan P. Young, Craig R. Stumpf, Joan Chen, Gary G. Chiang, Peggy A. Thompson, Kevin R. Webster. A focused CRISPR screen to identify synthetic lethal interactions with the novel eIF4A inhibitor eFT226 in KRAS driven NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4343.