jsr-a Journal of Scientific Reports-A 2687-6167 Kütahya Dumlupinar University 10.59313/jsr-a.1397224 Gene and Molecular Therapy Medical Biotechnology Diagnostics Bioengineering (Other) Gen ve Moleküler Tedavi Tıbbi Biyoteknolojik Tanılama Biyomühendislik (Diğer) Drug repurposing analysis with co-expressed genes identifies novel drugs and small molecules for bladder cancer https://orcid.org/0000-0002-5256-4778 Göv Esra ADANA ALPARSLAN TÜRKEŞ BİLİM VE TEKNOLOJİ ÜNİVERSİTESİ https://orcid.org/0000-0001-7948-5087 Kaynak Bayrak Gökçe İZMİR BAKIRÇAY ÜNİVERSİTESİ 03 31 2024 056 70 81 11 28 2023 02 01 2024 Copyright © 2020, Journal of Scientific Reports-A 2020 Journal of Scientific Reports-A

Bladder cancer (BC) is the fifth most common malignancy in humans and has poor survival rates. Although there is extensive research on the diagnosis and treatment of BC, novel molecular therapies are essential due to tumor recurrence. In this study, we aim to identify repurposed drugs or small molecules of BC with multi-omics systems biology perspective. Gene expression datasets were statistically analyzed by comparing bladder tumor and normal bladder tissues and differentially expressed genes (DEGs) were determined. Co-expression network of common DEGs for BC was constructed and co-expressed module was found by using tumors and control bladder tissues. Using independent data, we demonstrated the high prognostic capacity of the module genes. Moreover, repurposed drugs or small molecules were predicted by using L1000CDS2 gene expression based-search engine tool. We found numerous drug candidates as 480743.cdx, MK-2206, Geldanamycin, PIK-90, BRD-K50387473 (XMD8-92), BRD-K96144918 (mead acid), Vorinostat, PLX-4720, Entinostat, BIX-01294, PD-0325901 and Selumetinib, that may be used in BC therapy. We report 480743.cdx, BRD-K50387473 (XMD8-92) and mead acid as novel drugs or small molecules that offer crucial step in translational cancer research of BC.

 multi-omics data gene expression drug repurposing bladder cancer [1] Tang, C., Yu, M., Ma, J., and Zhu, Y, “Metabolic classification of bladder cancer based on multi‑omics integrated analysis to predict patient prognosis and treatment response”, J Transl Med, vol. 19 no. 205, 2021, doi: 10.1186/s13073-022-01056-4. [2] Yu, E.Y.-W., Zhang, H., Fu Y., et al, “Integrative multi-omics analysis for the determination of non-muscle invasive vs. muscle invasive bladder cancer: a pilot study”, Curr Oncol, vol. 29, no. 8, pp. 5442–5456, 2022, doi: 10.3390/curroncol29080430. [3] Mo, Q., Li, R, Adeegbe, D.O., Peng, G., and Chan, K.S., “Integrative multi-omics analysis of muscle-invasive bladder cancer identifies prognostic biomarkers for frontline chemotherapy and immunotherapy”, Commun Bıol. Vol. 3, no. 784, 2020, doi:10.1038/s42003-020-01491-2. [4] Lindskrog, S.V., Prip, F., Lamy, P., et al., “An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle invasive bladder cancer.”, Nat Commun., vol. 12, no. 2301, 2021. doi: 10.1038/s41467-021-22465-w. [5] Shi, Z.-D. Han, X.-X., Song, Z.-J., et al., “Integrative multi‑omics analysis depicts the methylome and hydroxymethylome in recurrent bladder cancers and identifies biomarkers for predicting PD‑L1 expression.”, Biomark. Res., vol. 11, no. 47, 2023, doi: 10.1186/s40364-023-00488-3. [6] Zhang, X., Wang, J., Lu, J. et al., “Robust prognostic subtyping of muscle-invasive bladder cancer revealed by deep learning-based multi-omics data integration”, Front. Oncol., vol. 11, no. 689626, 2021, doi.org/10.3389/fonc.2021.689626. [7] You, C., Piao, X.M., Kang, K., Kim, Y.J., and Kang, K., “Integrative transcriptome profiling reveals ska3 as a novel prognostic marker in non-muscle invasive bladder cancer.”, Cancers, vol. 13, no. 18, 4673, 2021, doi: 10.3390/cancers13184673. [8] Demirtas, T.Y., Rahman, R., Capkin Yurtsever, M., and Gov, E., “Forecasting gastric cancer diagnosis, prognosis, and drug repurposing with novel gene expression signatures.”, OMICS A J. Integr. Biol., vol. 26, no. 1, 2022, DOI:10.1089/omi.2021.0195. [9] Knowles, M.A., and Hurst, C.D., “Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity.”, Nat. Rev. Cancer, vol. 15, no. 1, pp. 25-41, 2014, doi: 10.1038/nrc3817. [10] Hurst, C.D., Cheng, G., and Platt, F.M., “Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight.”, Cell Rep. Med., vol. 2, 100472, 2021. [11] Goel, A., Ward, D.G., Noyvert, B., et al., “Combined exome and transcriptome sequencing of non‑muscle‑invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes.”, Genome Med., vol. 14, no. 59, 2022, doi: 10.1186/s13073-022-01056-4. [12] Gonzalez‑Fierro, A., Romo‑Perez, A., Chavez‑Blanco, A., Dominguez‑Gomez, G., and Duenas‑Gonzalez, A., “Does therapeutic repurposing in cancer meet the expectations of having drugs at a lower price?”, Clin. Drug Investig., vol. 43, no. 4, pp. 227–239, 2023, doi: 10.1007/s40261-023-01251-0. [13] Malik, J.A., Ahmed, S., Momin, S.S., et al. “Drug repurposing: A new hope in drug discovery for prostate cancer”, ACS Omega, vol. 8, no. 1, pp. 56−73, 2023, doi: 10.1021/acsomega.2c05821 [14] Feng, Y., Jia, B., and Shen, Z.,” Metformin and bladder cancer: Drug repurposing as a potential tool for novel therapy: A review”, Medicine, vol. 101, no. 45, 2022, doi: 10.1097/MD.0000000000031635. [15] Gao, X., Chen, Y., Chen, M., Wang, S., Wen, X., Zhang, S., “Identification of key candidate genes and biological pathways in bladder cancer.” Peer J, vol. 6, 2018, doi: 10.7717/peerj.6036. [16] Wang, J.P., Leng, J.Y., Zhang, R.K., Zhang, L., Zhang, B., Jiang, W.Y., Tong, L., “Functional analysis of gene expression profiling based prediction in bladder cancer.”, Oncol. Lett., vol. 15, no. 6, pp. 8417-8423, 2018, doi: 10.3892/ol.2018.8370. [17] Tang, F., He, Z., Lei, H., Chen, Y., Lu, Z., Zeng, G., Wang, H., “Identification of differentially expressed genes and biological pathways in bladder cancer”, Molecular Medicine Reports, vol. 17, no. 5, pp 6425-6434, 2018, doi: 10.3892/mmr.2018.8711. [18] Mengual, L, Burset, M, Ars, E, et al., “DNA microarray expression profiling of bladder cancer allows identification of noninvasive diagnostic markers.”, J Urol., vol. 182, no. 2, pp. 741-748, 2009, doi: 10.1016/j.juro.2009.03.084. [19] Zhang, Z., Furge, K.A., Yang, X.J., The, B.T., and Hansel, D.E., “Comparative gene expression profiling analysis of urothelial carcinoma of the renal pelvis and bladder.”, BMC Med Genom,. Vol. 3, no. 58, 2010, doi: 10.1186/1755-8794-3-58. [20] Barrett, T, Wilhite, S.E., Ledoux, P, et al., “NCBI GEO: Archive for functional genomics data sets-Update”, Nucleic Acids Res., 41(D1), D991–D995, 2013, doi: 10.1093/nar/gks1193. [21] Bolstad, B.M., Irizarry, R.A., Astrand, M., and Speed, T.P., “A comparison of normalization methods for high density oligonucleotide array data based on variance and bias.”, Bioinformatics, vol. 19, no. 2, pp. 185–193, 2013, doi: 10.1093/bioinformatics/19.2.185. [22] Gentleman, R., Carey, V.J., Huber, W., Irizarry, R.A., Dudoit, S., and Smyth, G.K. LIMMA: Linear models for microarray data. In: Bioinformatics and Computational Biology Solutions Using R and Bioconductor., eds. Springer: New York, New York, USA. 2005, pp. 397–420. [23] Zhou, Y., Zhou, B., Pache, L., et al., “Metascape provides a biologist-oriented resource for the analysis of systems-level datasets.”, Nat Commun, 10, 1523, 2019, https://doi.org/10.1038/s41467-019-09234-6. [24] Gov, E., and Arga, K.Y., “Differential co-expression analysis reveals a novel prognostic gene module in ovarian cancer.”, Sci Rep., vol. 7, no. 4996, 2017, doi:10.1038/s41598-017-05298-w [25] Saito, R, Smoot, M.E., Ono, K., et al., “A travel guide to Cytoscape plugins.”, Nat Methods, vol. 9, pp. 1069-1076, 2012, doi: 10.1038/nmeth.2212. [26] Cline, M.S., Smoot, M., Cerami, E., et al., “Integration of biological networks and gene expression data using Cytoscape”, Nat Protoc, vol. 2, pp. 2366–2382, 2007, doi:10.1038/nprot.2007.324 [27] Aguirre-Gamboa, R,, Gomez-Rueda, H., Martinez-Ledesma, E., et al., “SurvExpress: An online biomarker validation tool and database for cancer gene expression data using survival analysis.”, PLoS One, vol. 8, e74250, 2013, doi:10.1371/journal.pone.0074250 [28] Duan, Q., Reid, S.P., Clark, N.R., et al., “L1000CDS2: LINCSL1000 characteristic direction signatures search engine.”, NPJ Syst Biol Appl, vol. 2, no. 16015, 2016, doi:10.1038/npjsba.2016.15 [29] Kompier, L.C., Lurkin, I., van der Aa, M.N.M., et al., “FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy.” PLoS ONE, 5, vol. 11, e13821, 2010, doi: 10.1371/journal.pone.0013821. [30] Lai, W.T., Cheng, K.L., Baruchello, R., et al., “Hemiasterlin derivative (R)(S)(S)-BF65 and Akt inhibitor MK-2206 synergistically inhibit SKOV3 ovarian cancer cell growth.”, Biochem. Pharmacol., vol. 113, pp. 12–23, 2016, doi: 10.1016/j.bcp.2016.06.010. [31] Sathe, A., Guerth, F., Cronauer, M.V., et al., “Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy”, Br. J. Cancer, vol. 111, pp. 2103–2113, 2014, doi: 10.1038/bjc.2014.534. [32] Jonasch, E., Hasanov, E., Corn, P.G., et al., “A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma.”, Ann Oncol., vol. 28, pp. 804–808, 2017, doi: 10.1093/annonc/mdw676. [33] Lee, E.K., Tan-Wasielewski, Z., Aghajanian, C. et al., “Results of an abbreviated phase II study of AKT inhibitor MK-2206 in the treatment of recurrent platinum-resistant high grade serous ovarian, fallopian tube, or primary peritoneal carcinoma (NCT 01283035)”, Gynecol Oncol Rep., vol. 32, no. 100546, 2020, doi: 10.1016/j.gore.2020.100546 [34] Stover, E.H., Xiong, N., Myers, A.P., et al., “A phase II study of MK-2206, an AKT inhibitor, in uterine serous carcinoma.”, Gynecol Onc Rep., vol. 40, no. 100974, 2022, doi: 10.1016/j.gore.2022.100974. [35] Sun, D., Sawada, A., Nakashima, M., Kobayashi, T., Ogawa, O., and Matsui, Y., “MK2206 potentiates cisplatin-induced cytotoxicity and apoptosis through an interaction of inactivated Akt signaling pathway.”, Urol Oncol: Semin Orig., vol. 33, no. 3, e17-26, 2015, doi: 10.1016/j.urolonc.2014.10.018. [36] Sun, D, Wang, J, Zhang, H, et al., “MK2206 Enhances Cisplatin-Induced Cytotoxicity and Apoptosis in Testicular Cancer Through Akt Signaling Pathway Inhibition.”, Transl Oncol., vol. 13, no. 100769, 2020, doi: 10.1016/j.tranon.2020.100769. [37] Wang, J., Li, Z., Lin, Z., et al., “17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation.”, Cancer Lett., vol. 362, pp. 83-96, 2015, doi: 10.1016/j.canlet.2015.03.025. [38] Zeynali-Moghaddam, S., Mohammadian, M., Kheradmand, F., et al., “A molecular basis for the synergy between 17‑allylamino‑17‑demethoxy geldanamycin with Capecitabine and Irinotecan in human colorectal cancer cells through VEFG and MMP-9 gene expression.”, Gene, vol. 684, pp. 30–38, 2019, doi: 10.1016/j.gene.2018.10.016. [39] Liew, H.Y., Tan, X.Y., Chan, H.H., Khaw, K.Y., and Ong, Y.S., “Natural HSP90 inhibitors as a potential therapeutic intervention in treating cancers: A comprehensive review.”, Pharmacol Res., vol. 181, no. 106260, 2022, doi: 10.1016/j.phrs.2022.106260. [40] Parma, B., Wurdak, H., and Ceppi, P., “Harnessing mitochondrial metabolism and drug resistance in non-small cell lung cancer and beyond by blocking heat-shock proteins.”, Drug Resist Updat., vol. 65, no. 100888, 2022, doi: 10.1016/j.drup.2022.100888. [41] Germano, S, Barberis, D, Santoro, M.M., et al., “Geldanamycins trigger a novel ron degradative pathway, hampering oncogenic signaling.”, J Biol Chem., vol. 281, no. 31, pp. 21710-21719, 2006, doi:10.1074/jbc.M602014200 [42] Karkoulis, P.K., Stravopodis, D.J., Konstantakou, E.G., andVoutsinas, G.E., “Targeted inhibition of heat shock protein 90 disrupts multiple oncogenic signaling pathways, thus inducing cell cycle arrest and programmed cell death in human urinary bladder cancer cell lines.”, Cancer Cell Int., vol. 13, no. 11, 2013, doi.org/10.1186/1475-2867-13-11 [43] Tang, Y., Zhou, Y., Fan, S., Wen, Q., “The multiple roles and therapeutic potential of HSP60 in cancer.”, Biochem Pharmacol., vol. 201, no. 115096, 2022, https://doi.org/10.1016/j.bcp.2022.115096 [44] Dockx, Y, Vangestel, C, Van den Wyngaert, T., et al., “Early changes in [18F]FDG Uptake as a readout for PI3K/Akt/mTOR targeted drugs in HER-2-positive cancer xenografts.”, Mol Imaging., pp. 1-14, 2021, doi: 10.1155/2021/5594514. [45] Tong, Z., Sathe, A., Ebner, B., et al., “Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer.” J Exp Clin Cancer Res., vol. 38, no. 322, 2019, doi.org/10.1186/s13046-019-1322-9. [46] Sathe, A., Chalaud, G., Oppolzer, I., et al., “Parallel PI3K, AKT and mTOR inhibition is required to control feedback loops that limit tumor therapy.”, PloS one, 13, 1, e0190854, 2018, doi: 10.1371/journal.pone.0190854. [47] Le, V.K.H., Pham, T.P.D., and Truong, D.H., “Delivery systems for vorinostat in cancer treatment: An updated review.”, J Drug Deliv Sci Technol., vol. 61, no. 102334, 2021, https://doi.org/10.1016/j.jddst.2021.102334 [48] Ma, X., Wang, J., Lıu, J., et al., “Targeting CD146 in combination with vorinostat for the treatment of ovarian cancer cells.” Oncol Lett., vol. 13, pp. 1681-1687, 2017, doi: 10.3892/ol.2017.5630 [49] Okubo, K., Isono, M., Miyai, K., Asano, T., and Sato, A., “Fluvastatin potentiates anticancer activity of vorinostat in renal cancer cells.”, Cancer Sci., vol. 111, no. 1, pp. 112-126, 2020, doi: 10.1111/cas.14225. [50] Wawruszak, A., Borkiewicz, L., Okon, E., Kukula-Koch, W., Afshan, S., and Halasa, M., “Vorinostat (SAHA) and breast cancer: An overview.”, Cancers, vol. 13, no. 18, 2021, doi: 10.3390/cancers13184700. [51] Wang, D., Ouyang, S., Tian, Y., et al., “Intravesical treatment with Vorinostat can prevent tumor progression in MNU induced bladder cancer.”, J Cancer Ther., vol. 4, no 6, 2013, DOI: 10.4236/jct.2013.46A3001. [52] Kaletsch, A, Pinkerneil, M., Hoffmann, M.J., et al., “Effects of novel HDAC inhibitors on urothelial carcinoma cells.”, Clin Epigenetics., vol. 10, no. 100, 2018, https://doi.org/10.1186/s13148-018-0531-y. [53] Quinn, D.I., Tsao-Wei, D.D., Twardowski, P., et al., “Phase II study of the histone deacetylase inhibitor vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in recurrent or metastatic transitional cell carcinoma of the urothelium – an NCI-CTEP sponsored: California Cancer Consortium trial, NCI 6879.,” Investig New Drugs., no. 39, pp. 812-820, 2021, doi: 10.1007/s10637-020-01038-6. [54] Bekele, R.T., Samant, A.S., Nassar, A.H., “RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics.”, J Clin Invest., vol. 131, no. 22, 2021, doi: 10.1172/JCI147849. [55] Chen, Z., Zhao, Y., Tian, Y., Cao, R., Shang, D., “Pan-cancer analysis of the TRP family, especially TRPV4 and TRPC4, and its expression correlated with prognosis, tumor microenvironment, and treatment sensitivity.” Biomolecules, vol. 13, no. 282, 2023, doi: 10.3390/biom13020282. [56] Wang, L., de Oliveira, R.L., Huijberts, et al., “An acquired vulnerability of drug-resistant melanoma with therapeutic potential.” Cell., vol. 173, pp. 1413-1425, 2018, doi: 10.1016/j.cell.2018.04.012. [57] Capone, E., Lamolinara, A., D'Agostino, D., et al., “EV20-mediated delivery of cytotoxic auristatin MMAF exhibits potent therapeutic efficacy in cutaneous melanoma.” J Control Release., vol. 277, pp. 48-56, 2018, doi: 10.1016/j.jconrel.2018.03.016. [58] Rohde, S., Lindner, T., Polei, S., et al., “Application of in vivo imaging techniques to monitor therapeutic efficiency of PLX4720 in an experimental model of microsatellite instable colorectal cancer.”, Oncotarget., vol. 8, no. 41, pp. 69756-69767, 2017, doi: 10.18632/oncotarget.19263. [59] Pili, R., Salumbides, B., Zhao, M., et al., “Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours.” Br J Cancer., vol. 106, no. 1, pp. 77-84, 2012, doi: 10.1038/bjc.2011.527. [60] Truong, A.S., Zhou, M., Krishnan, B., et al., “Entinostat induces antitumor immune responses through immune editing of tumor neoantigens.” J Clin Invest., vol. 131, no. 6, 2021, doi: 10.1172/JCI138560. [61] Wang, C., Hamacher, A., Petzsch, P., et al., “Combination of Decitabine and Entinostat synergistically inhibits urothelial bladder cancer cells via activation of FoxO1.”, Cancers, vol. 12, no. 2, 2020, doi: 10.3390/cancers12020337. [62] Leblond, M., Zdimerova, H., Desponds, E., Verdeil, G., “Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy.”, Cancers, vol. 13, no. 18, 2021, doi: 10.3390/cancers13184712. [63] Cui, J., Sun, W., Hao, X., et al., “EHMT2 inhibitor BIX-01294 induces apoptosis through PMAIP1-USP9X-MCL1 axis in human bladder cancer cells.”, Cancer Cell Int., vol. 15, no. 4, 2015, doi: 10.1186/s12935-014-0149-x. [64] Cao, Y., Sun, J., Li, M., et al., “Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells.”, Acta Pharmacol Sin., vol. 40, pp. 1076-1084, 2019, doi:10.1038/s41401-018-0205-5 [65] Yang, Z., Wang, H., Zhang, N., et al., “Chaetocin Abrogates the self-renewal of bladder cancer stem cells via the suppression of the KMT1A–GATA3–STAT3 circuit.”, Front. Cell Dev. Biol., vol. 8, no. 424, 2020, doi: 10.3389/fcell.2020.00424. [66] Li F, Zeng J, Gao Y, Guan Z, Ma Z, Shi Q, et al., “G9a Inhibition Induces Autophagic Cell Death via AMPK/mTOR Pathway in Bladder Transitional Cell Carcinoma.”, PLoS ONE, vol. 10, no. 9, 2015, doi:10.1371/journal.pone.0138390. [67] Mourits, V.P., van Puffelen, J.H., Novakovic, B., et al., “Lysine methyltransferase G9a is an important modulator of trained immunity.”, Clin Trans Immunol., vol. 10, 2021, doi: 10.1002/cti2.1253. [68] Cirone, P., Andresen, C.J., Eswaraka, J.R., Lappin, P.B., and Bagi, C.M., “Patient derived xenografts reveal limits to PI3K/mTOR and MEK mediated inhibition of bladder cancer.”, Cancer Chemother Pharmacol., vol. 73, pp. 525-538, 2014, doi: 10.1007/s00280-014-2376-1. [69] Sim, W.J., Iyengar, P.V., Lama, D., et al., “c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression.”, Nat Commun., vol. 10, no. 1, 2019, doi: 10.1038/s41467-019-12241-2. [70] Zhang, Y., Zhang, Y., Lı, M., et al., “Combination of SB431542, CHIR99021 and PD0325901 has a synergic effect on abrogating valproic acid‑induced epithelial‑mesenchymal transition and stemness in HeLa, 5637 and SCC‑15 cells.”, Oncol Rep., vol. 41, pp. 3545-3554, 2019, doi: 10.3892/or.2019.7088. [71] Campagne, O., Yeo, K.K., Fangusaro, J., Stewart, C.F., “Clinical pharmacokinetics and pharmacodynamics of Selumetinib.”, Clin pharmacokinet., vol. 60, no. 3, pp. 283-303, 2021, doi: 10.1007/s40262-020-00967-y. [72] LoRusso, P.M., Infante, J.R., Kim, KB, et al., “A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors.”, BMC Cancer., vol. 17, no. 173, 2017, doi: 10.1186/s12885-017-3143-6. [73] Schulz, G.B., Elezkurtaj, S., Börding, T., et al., “Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer.”, Cancer Sci., vol. 112, pp. 1987-1996, 2021, doi: 10.1111/cas.14878 [74] Kinoshita, Y., Yoshizawa, K., Hamazaki, K., et al., “Dietary effects of mead acid on N-methyl-N-nitrosourea-induced mammary cancers in female Sprague-Dawley rats.”, Biomed Rep., vol. 4, pp. 33-39, 2016, doi: 10.3892/br.2015.530. [75] Kinoshita Y, Yoshizawa K, Hamazaki K, et al., “Mead acid inhibits the growth of KPL-1 human breast cancer cells in vitro and in vivo.”, Oncol Rep., vol. 32, pp. 1385-1394, 2014, DOI: 10.3892/or.2014.3390. [76] Farag, M.A., and Gad, M.Z., “Omega‑9 fatty acids: potential roles in inflammation and cancer management.”, J Genet Eng Biotechnol., vol. 20, no. 48, 2022, doi: 10.1186/s43141-022-00329-0. [77] Kang, C., Kim, J.S., Kim, C.Y., Kim, E.Y., and Chung, H.M., “The pharmacological inhibition of ERK5 enhances apoptosis in acute myeloid leukemia cells.”, Int J Stem Cells, vol. 11, no. 2, pp. 227-234, 2018, doi: 10.15283/ijsc18053. [78] Rovida, E., Di Maira, G., Tusa, I., et al., “The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma.”, Eur J Cancer., vol. 64, no. 9, pp. 1454-1465, 2015, doi: 10.1136/gutjnl-2014-306761. [79] Sureban, S.M., Maya, R., Weygant, N., et al., “XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism.”, Cancer Lett., vol. 351, pp. 151-161, 2014, doi: 10.1016/j.canlet.2014.05.011. [80] Yang, Q., Deng, X., Lu, B., et al., “Pharmacological inhibition of BMK1 suppresses tumor growth through PML.” Cancer Cell., vol. 18, no. 3, pp. 258-267, 2010, doi: 10.1016/j.ccr.2010.08.008.