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Abstract 6186: Identification of MYOF as a novel biomarker by using oxaliplatin-resistant gastric cancer organoid model


 Background: The prognosis of gastric cancer (GC) is improving due to the development of chemotherapy, however, intrinsic or acquired resistance to anti-cancer drugs is still a major clinical challenge. Oxaliplatin (L-OHP) is one of the anti-cancer drugs used as first-line treatment for GC. As with other anti-cancer drugs, although acquired resistance to L-OHP is a major problem, no biomarkers are clinically available for L-OHP response. Recently, cancer stem cells (CSCs) were shown to be involved in the acquisition of drug resistance. Hence, the major goal is to discover novel predictive biomarkers and overcome L-OHP resistance in GC in relation to CSCs.
 Methods: We used the organoid model; a culture method that allows 3D in vitro culturing of tissue-like structures and is presumed to contain many stem/progenitor cells. We established three independent L-OHP-resistant gastric cancer organoids (GCOs) by adding increasing doses of L-OHP in the culture medium over time. Gene expression profiles of the pairs of parental and resistant organoids were evaluated using microarray analysis. We analyzed the microarray data of L-OHP-resistant GCOs with our previous study from 5-fluorouracil (5-FU)-resistant GCOs (GSE154127). We validated the upregulated genes in the L-OHP-resistant GCOs by qRT-PCR. To confirm the use of upregulated genes as a novel biomarker, we immunohistochemically evaluated the expression levels in GC tissue samples. Furthermore, we analyzed the effects of knockdown using both GC cell lines and GCOs.
 Results: Through the comparison of the data, we detected myoferlin (MYOF) to be a candidate gene responsible only for L-OHP resistance. qRT-PCR results confirmed the results of the microarray and found that high expression of MYOF correlated significantly with the IC50 of L-OHP in GCOs. Immunohistochemistry analysis for MYOF using 132 GC cases showed that high expression of MYOF was significantly associated with poor prognosis, T grade, N grade, and lymphatic invasion, and showed MYOF to be an independent prognostic indicator, especially in the GC patients treated with platinum-based chemotherapy. The knockdown or inhibition of MYOF by WJ460 in GC cell line and GCOs enhanced L-OHP sensitivity while it reduced cell growth, spheroid/organoid formation, migration, invasion, and in vivo tumorigenesis.
 Conclusion: We highlight that MYOF is highly involved in L-OHP resistance and tumor progression in GC. Our results indicate that MYOF could be a promising biomarker in GC to predict L-OHP sensitivity and tumor progression and a potential candidate gene as a therapeutic target.
 Citation Format: Kenji Harada, Naoya Sakamoto, Shoichi Ukai, Tsuyoshi Takashima, Ryota Maruyama, Daiki Taniyama, Kazuaki Tanabe, Hideki Ohdan, Wataru Yasui. Identification of MYOF as a novel biomarker by using oxaliplatin-resistant gastric cancer organoid model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6186.