Similar articles

Abstract: Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.

阻断JAK2/STAT3和ERK通路诱发凋亡抑制胃肠道癌的增殖

[1]AndersonJL, TitzB, AkiyamaR, et al., 2014. Phosphoproteomic profiling reveals IL6-mediated paracrine signaling within the Ewing sarcoma family of tumors. Mol Cancer Res, 12(12):1740-1754.

[2]AnderssonE, KuusanmäkiH, BortoluzziS, et al., 2016. Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia. Leukemia, 30(5):1204-1208.

[3]AshrafizadehM, ZarrabiA, OroueiS, et al., 2020. STAT3 pathway in gastric cancer: signaling, therapeutic targeting and future prospects. Biology (Basel), 9(6):126.

[4]BlairHA, 2019. Fedratinib: first approval. Drugs, 79:1719-1725

[5]BoseP, VerstovsekS, 2017. JAK2 inhibitors for myeloproliferative neoplasms: what is next? Blood, 130(2):115-125.

[6]ChatterjeeN, BivonaTG, 2019. Polytherapy and targeted cancer drug resistance. Trends Cancer, 5(3):170-182.

[7]ChenWB, WuJH, ShiH, et al., 2014. Hepatic stellate cell coculture enables sorafenib resistance in Huh7 cells through HGF/c-Met/Akt and Jak2/Stat3 pathways. BioMed Res Int, 2014:764981.

[8]ChenYC, ChienLH, HuangBM, et al., 2016. Aqueous extracts of Toona sinensis leaves inhibit renal carcinoma cell growth and migration through JAK2/stat3, Akt, MEK/ERK, and mTOR/HIF-2α pathways. Nutr Cancer, 68(4):654-666.

[9]ColmegnaB, MorosiL, D'IncalciM, 2018. Molecular and pharmacological mechanisms of drug resistance: an evolving paradigm. Handb Exp Pharmacol, 249:1-12.

[10]DeerEL, González-HernándezJ, CoursenJD, et al., 2010. Phenotype and genotype of pancreatic cancer cell lines. Pancreas, 39(4):425-435.

[11]DegirmenciU, WangM, HuJC, 2020. Targeting aberrant RAS/RAF/MEK/ERK signaling for cancer therapy. Cells, 9(1):198.

[12]EzerskyteM, ParedesJA, MalvezziS, et al., 2018. O⁶-methylguanine-induced transcriptional mutagenesis reduces p53 tumor-suppressor function. Proc Natl Acad Sci USA, 115(18):4731-4736.

[13]GerberDE, 2008. Targeted therapies: a new generation of cancer treatments. Am Fam Physician, 77(3):311-319.

[14]GrimaldiAM, SimeoneE, FestinoL, et al., 2017. MEK inhibitors in the treatment of metastatic melanoma and solid tumors. Am J Clin Dermatol, 18(6):745-754.

[15]GronerB, von MansteinV, 2017. Jak Stat signaling and cancer: opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol, 451:1-14.

[16]GuoYJ, PanWW, LiuSB, et al., 2020. ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med, 19(3):1997-2007.

[17]HirataE, SahaiE, 2017. Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect Med, 7(7):a026781.

[18]HolohanC, van SchaeybroeckS, LongleyDB, et al., 2013. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer, 13(10):714-726.

[19]HuaF, LiK, ShangS, et al., 2019. Immune signaling and autophagy regulation. Adv Exp Med Biol, 1206:551-593.

[20]LiuQQ, ZengXL, GuanYL, et al., 2020. Verticillin A inhibits colon cancer cell migration and invasion by targeting c-Met. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(10):779-795.

[21]MeierjohannS, 2017. Crosstalk signaling in targeted melanoma therapy. Cancer Metastasis Rev, 36(1):23-33.

[22]MeyerSC, 2017. Mechanisms of resistance to JAK2 inhibitors in myeloproliferative neoplasms. Hematol Oncol Clin North Am, 31(4):627-642.

[23]MizukamiT, TogashiY, SogabeS, et al., 2015. EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition. Int J Oncol, 47(2):499-505.

[24]MokhtariRB, HomayouniTS, BaluchN, et al., 2017. Combination therapy in combating cancer. Oncotarget, 8(23):38022-38043.

[25]NieYZ, WuKC, YuJ, et al., 2017. A global burden of gastric cancer: the major impact of China. Expert Rev Gastroenterol Hepatol, 11(7):651-661.

[26]PardananiA, HarrisonC, CortesJE, et al., 2015. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol, 1(5):643-651.

[27]PencikJ, PhamHTT, SchmoellerlJ, et al., 2016. JAK-STAT signaling in cancer: from cytokines to non-coding genome. Cytokine, 87:26-36.

[28]PourhoseingholiMA, VahediM, BaghestaniAR, 2015. Burden of gastrointestinal cancer in Asia; an overview. Gastroenterol Hepatol Bed Bench, 8(1):19-27.

[29]RamamonjisoaN, AckerstaffE, 2017. Characterization of the tumor microenvironment and tumor‒stroma interaction by non-invasive preclinical imaging. Front Oncol, 7:3.

[30]SamatarAA, PoulikakosPI, 2014. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov, 13(12):928-942.

[31]SchizasD, CharalampakisN, KoleC, et al., 2020. Immunotherapy for pancreatic cancer: a 2020 update. Cancer Treat Rev, 86:102016.

[32]ThambiP, SausvilleEA, 2002. STI571 (imatinib mesylate): the tale of a targeted therapy. Anticancer Drugs, 13(2):111-114.

[33]VerstovsekS, GotlibJ, MesaRA, et al., 2017. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol, 10:156.

[34]VertG, ChoryJ, 2011. Crosstalk in cellular signaling: background noise or the real thing? Dev Cell, 21(6):985-991.

[35]WangLH, WuCF, RajasekaranN, et al., 2018. Loss of tumor suppressor gene function in human cancer: an overview. Cell Physiol Biochem, 51(6):2647-2693.

[36]WuQY, MaMM, FuL, et al., 2018. Roles of germline JAK2 activation mutation JAK2 V625F in the pathology of myeloproliferative neoplasms. Int J Biol Macromol, 116:1064-1073.

[37]WuQY, MaMM, ZhangS, et al., 2019. Disruption of R867 and Y613 interaction plays key roles in JAK2 R867Q mutation caused acute leukemia. Int J Biol Macromol, 136:209-219.

[38]XinP, XuXY, DengCJ, et al., 2020. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol, 80:106210.

[39]ZhangJY, TianXJ, XingJH, 2016. Signal transduction pathways of EMT induced by TGF-β, SHH, and WNT and their crosstalks. J Clin Med, 5(4):41.

[40]ZhangQ, ZhangY, DiamondS, et al., 2016. The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke’s encephalopathy. Drug Metabo Dispos, 42(10):1656-1662.