Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Transcriptome analysis of iBET-151, a BET inhibitor alone and in combination with paclitaxel in gastric cancer cells

  • Kang, Sun Kyoung (Songdang Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Bae, Hyun Joo (Songdang Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Kwon, Woo Sun (Songdang Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Che, Jingmin (Songdang Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Kim, Tae Soo (Songdang Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Chung, Hyun Cheol (Songdang Institute for Cancer Research, Yonsei University College of Medicine) ;
  • Rha, Sun Young (Songdang Institute for Cancer Research, Yonsei University College of Medicine)
  • Received : 2020.11.24
  • Accepted : 2020.12.18
  • Published : 2020.12.31
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Abstract

BET inhibitor, as an epigenetic regulator inhibitor, reduces the expression of oncogenes such as Myc and Bcl-2, which affects cancer growth and development. However, it has modest activity because of the narrow therapeutic index. Therefore, combination therapy is necessary to increase the anti-tumor effect. Paclitaxel, an anti-mitotic inhibitor, is used as second-line therapy for gastric cancer (GC) as a monotherapy or combination. In this study, we performed RNA sequencing of GC cells treated with iBET-151 and/or paclitaxel to identify the differentially expressed genes associated with possible mechanisms of synergistic effect. We also performed Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses to determine the most enriched terms and pathways of upregulated and downregulated genes. We found 460 genes in which iBET-151 and paclitaxel combination treatment changed more than single-treatment or no-treatment. Thus, additional functional studies are needed, but our results provide the first evidence of the synergistic effect between iBET-151 and paclitaxel in regulating the transcriptome of GC cells.

Keywords

Acknowledgement

We thank all members of the CMRC lab for discussion. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020R1A2B5B02001452).

References

  1. Kim HJ, Kang SK, Kwon WS, Kim TS, Jeong I, Jeung HC, et al. Forty-nine gastric cancer cell lines with integrative genomic profiling for development of c-MET inhibitor. Int J Cancer 2018;143:151-159. https://doi.org/10.1002/ijc.31304
  2. Ajani JA, Lee J, Sano T, Janjigian YY, Fan D, Song S. Gastric adenocarcinoma. Nat Rev Dis Primers 2017;3:17036. https://doi.org/10.1038/nrdp.2017.36
  3. Fu DG. Epigenetic alterations in gastric cancer (review). Mol Med Rep 2015;12:3223-3230. https://doi.org/10.3892/mmr.2015.3816
  4. Hong S, Won YJ, Park YR, Jung KW, Kong HJ, Lee ES, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2017. Cancer Res Treat 2020;52:335-350. https://doi.org/10.4143/crt.2020.206
  5. Ahn HK, Jang J, Lee J, Se Hoon P, Park JO, Park YS, et al. P21-activated kinase 4 overexpression in metastatic gastric cancer patients. Transl Oncol 2011;4:345-349. https://doi.org/10.1593/tlo.11145
  6. Ang YL, Yong WP, Tan P. Translating gastric cancer genomics into targeted therapies. Crit Rev Oncol Hematol 2016;100:141-146. https://doi.org/10.1016/j.critrevonc.2016.02.007
  7. Chia DK, So JB. Recent advances in intra-peritoneal chemotherapy for gastric cancer. J Gastric Cancer 2020;20:115-126. https://doi.org/10.5230/jgc.2020.20.e15
  8. Bang YJ, Xu RH, Chin K, Lee KW, Park SH, Rha SY, et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017;18:1637-1651. https://doi.org/10.1016/S1470-2045(17)30682-4
  9. Shi J, Mitchison TJ. Cell death response to anti-mitotic drug treatment in cell culture, mouse tumor model and the clinic. Endocr Relat Cancer 2017;24:T83-T96. https://doi.org/10.1530/ERC-17-0003
  10. Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018;392:123-133. https://doi.org/10.1016/S0140-6736(18)31257-1
  11. Guideline Committee of the Korean Gastric Cancer Association (KGCA), Development Working Group & Review Panel. Korean Practice Guideline for Gastric Cancer 2018: an evidence-based, multi-disciplinary approach. J Gastric Cancer 2019;19:1-48. https://doi.org/10.5230/jgc.2019.19.e8
  12. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014;15:1224-1235. https://doi.org/10.1016/S1470-2045(14)70420-6
  13. Orenay-Boyacioglu S, Kasap E, Gerceker E, Yuceyar H, Demirci U, Bilgic F, et al. Expression profiles of histone modification genes in gastric cancer progression. Mol Biol Rep 2018;45:2275-2282. https://doi.org/10.1007/s11033-018-4389-z
  14. Kasai S, Sasaki T, Watanabe A, Nishiya M, Yasuhira S, Shibazaki M, et al. Bcl-2/Bcl-xL inhibitor ABT-737 sensitizes pancreatic ductal adenocarcinoma to paclitaxel-induced cell death. Oncol Lett 2017;14:903-908. https://doi.org/10.3892/ol.2017.6211
  15. Costa-Silva J, Domingues D, Lopes FM. RNA-Seq differential expression analysis: an extended review and a software tool. PLoS One 2017;12:e0190152. https://doi.org/10.1371/journal.pone.0190152
  16. Zhu Z, Chen D, Zhang W, Zhao J, Zhi L, Huang F, et al. Modulation of alternative splicing induced by paclitaxel in human lung cancer. Cell Death Dis 2018;9:491. https://doi.org/10.1038/s41419-018-0539-4
  17. Huang G, Zhu G. Sirtuin-4 (SIRT4), a therapeutic target with oncogenic and tumor-suppressive activity in cancer. Onco Targets Ther 2018;11:3395-3400. https://doi.org/10.2147/OTT.S157724
  18. Kurimchak AM, Shelton C, Duncan KE, Johnson KJ, Brown J, O'Brien S, et al. Resistance to BET bromodomain inhibitors is mediated by Kinome reprogramming in ovarian cancer. Cell Rep 2016;16:1273-1286. https://doi.org/10.1016/j.celrep.2016.06.091
  19. Chua V, Orloff M, Teh JL, Sugase T, Liao C, Purwin TJ, et al. Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma. EMBO Mol Med 2019;11:e9081.