Abstract LB-094: Suppression of inflammatory gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer

Abstract

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEK inhibition we identified gene expression differences between MEKi-sensitive and MEKi-resistant colorectal cancer cell lines. Strikingly, inflammation-related gene sets were the most significantly enriched in cell lines exhibiting intrinsic or acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed inflammatory gene expression and in combination with MEK inhibitors displayed synergistic anti-proliferative activity, inhibited colony formation and induced apoptosis in colorectal cancer cell lines. NFkB activation was greater in cell lines resistant to MEK inhibition and JQ1 treatment suppressed TNF-induced translocation of NFkB to the nucleus. Resistance to MEK inhibition could be induced by inflammatory cytokines or by conditioned medium from macrophage cultures and was associated with greater NFkB activation. In 2-dimensional cell culture and in 3-dimensional spheroid models of colorectal cancer, resistance to trametinib was readily established; however, co-treatment of cells with JQ1 and trametinib suppressed the emergence of resistant populations. Notably, high inflammatory gene expression was confirmed in patient-derived organoid (PDO) models of colorectal cancer, which displayed resistance to trametinib. JQ1 treatment of PDOs suppressed inflammatory gene expression and showed synergistic anti-proliferative activity in combination with trametinib. Combination treatment of in vivo models of KRAS-mutant colorectal cancer significantly suppressed tumor growth. Our findings provide a potential explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, where a highly inflammatory environment may prime cells to be resistant to MEK inhibition. Moreover, the high expression of inflammatory genes was associated with significantly reduced survival of colorectal cancer patients. Excitingly, this opens novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer. Citation Format: Steve Wagner, George Vlachogiannis, Alexis de Haven Brandon, Melanie Valenti, Gary Box, Liam Jenkins, Caterina Mancusi, Annette Self, Ritika Chauhan, Alistair Rust, Nik Matthews, Kate Eason, Anguraj Sadanandam, Clare Isacke, Vladimir Kirkin, Nicola Valeri, Steven R. Whittaker. Suppression of inflammatory gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-094.