Abstract
Abstract Background: RAS activity might play crucial roles in the aggravation of KRAS-mutated pancreatic cancer (PC), including systemic inflammatory reactions, tumor-driven inflammation, chemo-refractoriness and anorexia. We aimed to identify RAS activity-related features in PC patients with liver metastasis (LM), to create a murine xenograft model of human PC cells representative of RAS-driven aggravation. Methods: RAS activities in 77 patients who underwent needle biopsy for LM of treatment-naïve PC were measured using an RAS signature score from a comprehensive cDNA microarray dataset of LM samples. Changes in the sum of the longest diameter of the target lesion in the first month of chemotherapy (ΔSLD), laboratory data and anorexia score at baseline were evaluated. Gene modules to be correlated with RAS activity and aggravation were evaluated using weighted co-expression network analysis (WGCNA). Human PC cells were classified as high and low activity according to in silico analysis of the DepMap CCLE expression dataset for profiling RAS activity and the best hub gene expression in the gene module. Subcutaneous xenograft models of human PC cells with high and low activity in severe combined immunodeficiency mice were compared to explore the RAS-related phenotype. Results: KRAS-mutated LM was detected in 70 of the 77 PC patients (90.9%). RAS signatures were up-regulated in patients with KRAS-mutated LM (P < 0.01), high serum level of C-reactive protein (P = 0.01) as a systemic inflammatory marker, high expression of IL-6 mRNA by the tumor (P = 0.12) as an index of tumor-driven inflammation, and high level of phospho-Erk (P = 0.03). In 58 PC patients receiving first-line chemotherapy for KRAS-mutated LM, ΔSLD in patients with a high RAS signature was increased as compared to those in patients with a low RAS signature (P = 0.045). WGCNA methods revealed that the green module highly correlated with RAS activity and aggravation. Based on in silico analysis with classification of the human PC cell lines CFPAC-1 and SUIT-2 into high and low activity cells, respectively, CFPAC-1 tumors showed desmoplasia and high expression of tumor IL-6 and liver SAA1 as compared to SUIT-2 tumors (P = 0.046 and P = 0.016, respectively). Conclusions: Tumor RAS activity is related to inflammation-related aggravation in PC patients. RAS-related inflammation can be accurately presented in a murine model of human PC cells, which might be an effective tool to test the inhibition of RAS-driven inflammation. Citation Format: Shuichi Mitsunaga, Mari Masuda, Hiroki Yoshimatsu, Yoichi Kamei, Mitsuhito Sasaki, Kazuo Watanabe, Masafumi Ikeda. RAS activity-related features of metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2238.
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