Abstract
Abstract The tumor microenvironment is recognized as developing crosstalk between different cells by secretion of growth factors and cytokines, thus providing oncogenic signals enhancing tumor progression and drug resistance. Here, we hypothesized that tumor cells carrying KRAS mutation-induced cytokines may have a critical role in intercellular communication between microenvironment and tumor cells. We first investigated biologic evidence of secreted cytokines in KRAS mutant type (KRAS MT) cell lines. We explored the roles of cytokine that cell morphology, colony-formation ability, and wound-healing ability were enhanced when KRAS wild-type (KRAS WT) cell lines were exposed to conditioned media (CM) from KRAS MT cells, and we found macrophage migration inhibitory factor (MIF) was highly expressed in KRAS MT cells by analysis of proteomics. We also observed secreted MIF level between KRAS WT and MT cell lines, and it was highly secreted in KRAS MT cell lines. In addition, compared with patients whose KRAS mutation was not harbored, MIF expression was higher in patients who have KRAS mutation. The predictive marker of KRAS mutation in colorectal cancer patients is associated with resistance to antiepidermal growth factor receptor (EGFR) antibody cetuximab. Following the hypothesis, we investigated that secreted cytokines have an effect on the cetuximab resistance to surrounding cells including KRAS WT cells. Treatment of CM from KRAS MT cells led to cetuximab resistance in KRAS WT cells and MIF blockade prevented cetuximab resistance. Also, CM from knockout in KRAS MT cells by using CRISPR/Cas9 system resulted in sensitizing to cetuximab resistance compared with CM from KRAS MT cells. In conclusion, we demonstrated for the first time that MIF promotes the cetuximab resistance of KRAS WT colorectal cancer cells, and this effect is mediated by paracrine and autocrine signaling-induced activation of the intracellular AKT signaling pathways and regulated by NF-kb transcription factor through oncogenic KRAS mutation and MIF overexpression, respectively. These findings suggest that MIF may be a promising predictive biomarker for the cetuximab resistance of KRAS wild-type colorectal cancer patients. Citation Format: Jee Eun Jang, Hwang-Phill Kim, Sae Won Han, Tae You Kim. Mutant KRAS-induced macrophage migration inhibitory factor (MIF) secretion promotes resistance to cetuximab in colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B100.
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