Abstract 1955: Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth

Mutations in KRAS are among the most common oncogenic lesions across a variety of human cancers. Activation of KRAS directs signaling via the MAPK and PI3K pathways to promote tumor growth. One outcome of enhanced KRAS signaling is the induction of mRNA translation by eIF4A, eIF4E, and eIF4G, which together comprise the eIF4F complex. eIF4A is an RNA helicase that functions to unwind elements in the 59-untranslated region (UTR) of mRNAs to facilitate scanning of the 40S ribosomal subunit. eFT226 is a highly potent and selective inhibitor of eIF4A that functions by forming a ternary complex between eIF4A, eFT226 and specific polypurine motifs in the 59-UTR of select mRNAs, thus blocking ribosome scanning and inhibiting mRNA translation. This polypurine sequence motif is highly enriched in the 59-UTR of eFT226 target genes, many of which are known proto-oncogenes. Translational profiling revealed KRAS to be a target of eFT226 and 59-UTR sequence analysis of KRAS mRNA identified the polypurine regulatory motif, which imparts sensitivity to eFT226 mediated inhibition of translation. In cell-based reporter assays used to monitor translation, mutation of the KRAS 59-UTR polypurine motifs resulted in a 10-fold decrease in sensitivity to eFT226 relative to the wild-type sequence. In a cell panel screen for in vitro apoptosis induction by eFT226, the most sensitive models were enriched for cell lines driven by KRAS mutations. Consistent with these results, treatment with eFT226 decreased KRAS protein levels, repressed downstream MAPK signaling, inhibited cell proliferation, and induced apoptosis in a collection of non-small cell lung, colorectal and pancreatic KRAS mutant cancer cell lines. The ability of eFT226 to block tumor cell growth and induce apoptosis is independent of the specific KRAS mutation present (e.g. G12C/V, G13D, Q61H/L) suggesting that eFT226 could be broadly efficacious in treating tumors with activating KRAS mutations. Treatment of KRAS mutant solid tumor xenografts with eFT226 as a monotherapy significantly inhibited tumor growth. Together, these results highlight the ability of eFT226 to inhibit growth and promote apoptosis in KRAS mutant tumors and support the clinical development of eFT226 in KRAS driven tumors. A clinical trial evaluating eFT226 in patients with solid tumor malignancies has initiated. Citation Format: Craig R. Stumpf, Vikas K. Goel, Joan Chen, Jocelyn Staunton, Emily M. Santori, Maria Barrera, Haleigh Howard, Kevin R. Webster, Gary G. Chiang, Peggy A. Thompson. Inhibition of eIF4A by eFT226 blocks KRAS mutant tumor growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1955.