JAK/STAT信号通路在肺癌中的研究进展
|
摘要
Janus激酶(Janus kinase, JAK)/信号转导子和转录活化子(signal transducer and activator of transcription,STAT)信号通路是细胞因子信号传导的下游通路,调控细胞的发育、分化、增殖、凋亡等,不仅参与调节正常的生理过程,在肿瘤的发生发展中也起着重要作用,尤其是在血液系统肿瘤中意义重大。近年来,随着对JAK/STAT信号通路研究的深入,人们发现该通路在实体肿瘤的发生发展中也扮演关键角色。本文就近年来JAK/STAT信号通路参与肺癌发生发展、肺癌转移、肺癌耐药机制形成以及靶向该通路的抑制剂在肺癌治疗中的应用现状进行综述。
Janus kinase(JAK)/signal transducer and activator of transcription(STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer.
Janus kinase(JAK)/signal transducer and activator of transcription(STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer.
引文
[1]O'Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity immunodeficiency, and cancer. N Engl J Med, 2013, 368(2):161-170. doi:10.1056/NEJMra1202117
[2]Tan WL, Jain A, Takano A, et al. Novel therapeutic targets on the horizon for lung cancer. Lancet Oncol, 2016,17(8):e347-e362. doi:10.1016/S1470-2045(16)30123-1
[3]Leonard WJ, O'Shea JJ. Jaks and STATs:biological implications. Annu RevImmunol, 1998, 16:293-322. doi:10.1146/annurev.immunol.16.1.293
[4]Xu Y, Jin J, Xu J, et al. JAK2 variations and functions in lung adenocarcinoma. Tumour Biol, 2017, 39(6):1010428317711140. doi:10.1177/1010428317711140
[5]Li SD, Ma M, Li H, et al. Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications.Genome Med, 2017,9(1):89. doi:10.1186/s13073-017-0478-1
[6]Liu D, Huang Y, Zhang L, et al. Activation of Janus kinase 1 confers poor prognosis in patients with non-small cell lung cancer. Oncol Lett, 2017,14(4):3959-3966. doi:10.3892/ol.2017.6690
[7]Kachroo P, Lee MH, Zhang L, et al. IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer. J Exp Clin Cancer Res, 2013, 32:97.doi:10.1186/1756-9966-32-97
[8]Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer, 2004, 4(2):97-105. doi:10.1038/nrcl275
[9]Sanchez-Ceja SG, Reyes-Maldonado E, Vazquez-Manriquez ME, et al.Differential expression of STAT5 and Bcl-xL, and high expression of Neu and STAT3 in non-small-cell lung carcinoma. Lung Cancer,2006, 54(2):163-168. doi:10.1016/j.lungcan.2006.07.012
[10]Lu ZJ, Kang JB. STATs family expression in non-small cell lung cancer tissue and their potential target genes. Hainan Yi Xue Yuan Xue Bao, 2017, 23(6):732-735.[路泽军,康静波.STATs家族在非小细胞肺癌组织中的表达量分析及其潜在靶基因的研究.海南医学院学报,2017, 23(6):732-735.] doi:10.13210/j.cnki.jhmu.20161229.006
[11]Pastuszak-Lewandoska D, Domanska-Senderowska D, Kordiak J, et al.Immunoexpression analysis of selected JAK/STAT pathway molecules in patients with non-small-cell lung cancer. Pol Arch Intern Med, 2017,127(11):758-764. doi:10.20452/pamw.4115
[12]Zhao JL, Sun XR, Ji DX, et al. Influence of STAT1 on proliferation and IFN-βsensitivity of human non-small-cell lung cancer H1299 cells. Chinese Journal of Pathophysiology, 2015, 31(5):852-856.[赵嘉璐,孙筱茹,季东翔,等.STAT1对人非小细胞肺癌H1299细胞增殖及IFN-β敏感性的影响.中国病理生理杂志,2015,31(5):852-856.]doi:10.3969/j.issn.1000-4718.2015.05.015
[13]Ma Y, Chen JJ, Chen CS, et al. Effect of STAT1 gene transfection on human lung carcinoma xenograft growth in nude mice. Wenzhou Yi Xue Yuan Xue Bao, 2013, 43(7):461-463.[马源,陈俊杰,陈成水,等.STAT1基因转染对人肺腺癌裸鼠移植瘤生长的影响.温州医学院学报,2013, 43(7):461-463.] doi:10.3969/j.issn.1000-2138.2013.07.010
[14]Wu P, Wu D, Zhao L, et al. Prognostic role of STAT3 in solid tumors:a systematic review and meta-analysis. Oncotarget, 2016, 7(15):19863-19883.doi:10.18632/oncotarget.7887
[15]Xu YH, Lu S. A meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with non-small-cell lung cancer. Eur J Surg Oncol,2014,40(3):311-317. doi:10.1016/j.ejso.2013.11.012
[16]Tong M, Wang J, Jiang N, et al. Correlation between p-STAT3overexpression and prognosis in lung cancer:A systematic review and meta-analysis. PLoS One, 2017, 12(8):e0182282. doi:10.1371/journal.pone.0182282
[17]Grabner B, Schramek D, Mueller KM, et al. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat Commun, 2015, 6:6285.doi:10.1038/ncomms7285
[18]Jiang R, Jin Z, Liu Z, et al. Correlation of activated STAT3 expression with clinicopathologic features in lung adenocarcinoma and squamous cell carcinoma. Mol Diagn Ther, 2011, 15(6):347-352. doi:10.2165/11599190-000000000-00000
[19]Sun Y, Han Y, Wang X, et al. Correlation of EGFR Del 19 with Fn14/JAK/STAT signaling molecules in non-small cell lung cancer. Oncol Rep, 2016,36(2):1030-1040. doi:10.3892/or.2016.4905
[20]Chuang CH, Greenside PG, Rogers ZN, et al. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 2017, 23(3):291-300. doi:10.1038/nm.4285
[21]Lin HY, Chiang CH, Hung WC. STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. Br J Cancer, 2013, 109(3):731-738. doi:10.1038/bjc.2013.349
[22]Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA, 2014,311(19):1998-2006. doi:10.1001/jama.2014.3741
[23]Bivona TG, Doebele RC. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med, 2016, 22(5):472-478. doi:10.1038/nm.4091
[24]Yao Z, Fenoglio S, Gao DC, et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci U S A, 2010, 107(35):15535-15540. doi:10.1073/pnas. 1009472107
[25]Kim SM, Kwon OJ, Hong YK, et al. Activation of IL-6R/JAK1/STAT3signaling induces de novo resistance to irreversible EGFR inhibitors in nonsmall cell lung cancer with T790M resistance mutation. Mol Cancer Ther,2012,11(10):2254-2264. doi:10.1158/1535-7163.MCT-12-0311
[26]Gao SP, Chang Q, Mao N, et al. JAK2 inhibition sensitizes resistant EGFRmutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal, 2016,9(421):ra33. doi:10.1126/scisignal.aac8460
[27]Chiu HC, Chou DL, Huang CT,et al. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochem Pharmacol,2011,81(11):1263-1270. doi:10.1016/j.bcp.2011.03.003
[28]Blakely CM, Pazarentzos E, Olivas V, et al. NF-KB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep, 2015, 11(1):98-110. doi:10.1016/j.celrep.2015.03.012
[29]Lee HJ, Zhuang G, Cao Y, et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell, 2014, 26(2):207-221.doi:10.1016/j.ccr.2014.05.019
[30]Yu HA, Perez L, Chang Q, et al. A Phase 1/2 trial of ruxolitinib and erlotinib in patients with EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib. J Thorac Oncol, 2017,12(1):102-109. doi:10.1016/j.jtho.2016.08.140
[31]Leroy E, Constantinescu SN. Rethinking JAK2 inhibition:towards novelstrategies of more specific and versatile janus kinase inhibition. Leukemia,2017,31(5):1023-1038. doi:10.1038/leu.2017.43
[32]Tavallai M, Booth L, Roberts JL, et al. Rationally repurposing ruxolitinib(Jakafi((?)))as a solid tumor therapeutic. Front Oncol, 2016, 6:142. doi:10.3389/fonc.2016.00142
[33]Hu Y, Hong Y, Xu Y, et al. Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC. Apoptosis, 2014, 19(11):1627-1636. doi:10.1007/s10495-014-1030-z
[34]Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell, 2009,16(6):487-497. doi:10.1016/j.ccr.2009.10.015
[35]Xin H, Herrmann A, Reckamp K, et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res, 2011, 71(21):6601-6610.doi:10.1158/0008-5472.CAN-11-1217
[36]Lee JH, Park KS, Alberobello AT, et al. The Janus kinases inhibitor AZD 1480attenuates growth of small cell lung cancers in vitro and in vivo. Clin Cancer Res, 2013,19(24):6777-6786. doi:10.1158/1078-0432.CCR-13-1110
[37]Murakami T, Takigawa N, Ninomiya T, et al. Effect of AZD 1480 in an epidermal growth factor receptor-driven lung cancer model. Lung Cancer,2014,83(1):30-36. doi:10.1016/j.lungcan.2013.10.011
[38]Plimack ER, Lorusso PM, McCoon P, et al. AZD 1480:a phase I study of a novel JAK2 inhibitor in solid tumors. Oncologist, 2013, 18(7):819-820.doi:10.1634/theoncologist.2013-0198
[39]Kamran MZ, Patil P, Shirsath K, et al. Tyrosine kinase inhibitor AG490inhibits the proliferation and migration and disrupts actin organization of cancer cells. J Environ Pathol Toxicol Oncol, 2013, 32(4):361-371. doi:10.1615/JEnvironPatholToxicolO ncol.2013010051
[40]Zhao M, Liu F, Wang JY, et al. Effects of JAK2/STAT3 signaling pathway on angiogenesis in non-small cell lung cancer. Zhonghua Yi Xue Za Zhi,2011(6):375-381.[赵美,刘峰,王炯轶,等,JAK2/STAT3信号通路对非小细胞肺癌血管生成的影响.中华医学杂志,2011(6):375-381.] doi:10.3760/cma.j.issn.0376-2491.2011.06.004
[41]Liu RY, Zeng Y, Lei Z, et al. JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol,2014, 44(5):1643-1651.doi:10.3892/ijo.2014.2310
[42]Zhang X, Yue P, Page BD, et al. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci U S A, 2012, 109(24):9623-9628. doi:10.1073/pnas.1121606109
[43]JSM R, Aminudin N, Abd MSN. Chalepin:A compound from ruta angustifolia L. pers exhibits cell cycle arrest at S phase, suppresses nuclear factor-kappa B(NF-κB)pathway, signal transducer and activation of transcription 3(STAT3)phosphorylation and extrinsic apoptotic pathway in non-small cell lung cancer carcinoma(A549). Pharmacogn Mag, 2017,13(Suppl 3):S489-S498. doi:10.4103/pm.pm_13_17
[44]Blaskovich MA, Sun J, Cantor A, et al. Discovery of JSI-124(cucurbitacinⅠ), a selective Janus kinase/signal transducer and activator of transcription3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res, 2003, 63(6):1270-1279.
[45]Guo H, Kuang S, Song QL, et al. Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments. Acta Pharmacol Sin, 2018, 39(3):425-437. doi:10.1038/aps.2017.99
[46]Wong AL, Soo RA, Tan DS, et al. PhaseⅠand biomarker study of OPB-51602, a novel signal transducer and activator of transcription(STAT)3 inhibitor, in patients with refractory solid malignancies. Ann Oncol, 2015,26(5):998-1005. doi:10.1093/annonc/mdv026
[47]Pfeiffer M, Hartmann T N, Leick M, et al. Alternative implication of CXCR4in JAK2/STAT3 activation in small cell lung cancer. British journal of cancer, 2009, 100(12):1949. doi:10.1038/sj.bjc.6605068
[48]Harada D, Takigawa N, Ochi N, et al. JAK 2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. Cancer science, 2012, 103(10):1795-1802. doi:10.1111/j.1349-7006.2012.02363.x
[2]Tan WL, Jain A, Takano A, et al. Novel therapeutic targets on the horizon for lung cancer. Lancet Oncol, 2016,17(8):e347-e362. doi:10.1016/S1470-2045(16)30123-1
[3]Leonard WJ, O'Shea JJ. Jaks and STATs:biological implications. Annu RevImmunol, 1998, 16:293-322. doi:10.1146/annurev.immunol.16.1.293
[4]Xu Y, Jin J, Xu J, et al. JAK2 variations and functions in lung adenocarcinoma. Tumour Biol, 2017, 39(6):1010428317711140. doi:10.1177/1010428317711140
[5]Li SD, Ma M, Li H, et al. Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications.Genome Med, 2017,9(1):89. doi:10.1186/s13073-017-0478-1
[6]Liu D, Huang Y, Zhang L, et al. Activation of Janus kinase 1 confers poor prognosis in patients with non-small cell lung cancer. Oncol Lett, 2017,14(4):3959-3966. doi:10.3892/ol.2017.6690
[7]Kachroo P, Lee MH, Zhang L, et al. IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer. J Exp Clin Cancer Res, 2013, 32:97.doi:10.1186/1756-9966-32-97
[8]Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer, 2004, 4(2):97-105. doi:10.1038/nrcl275
[9]Sanchez-Ceja SG, Reyes-Maldonado E, Vazquez-Manriquez ME, et al.Differential expression of STAT5 and Bcl-xL, and high expression of Neu and STAT3 in non-small-cell lung carcinoma. Lung Cancer,2006, 54(2):163-168. doi:10.1016/j.lungcan.2006.07.012
[10]Lu ZJ, Kang JB. STATs family expression in non-small cell lung cancer tissue and their potential target genes. Hainan Yi Xue Yuan Xue Bao, 2017, 23(6):732-735.[路泽军,康静波.STATs家族在非小细胞肺癌组织中的表达量分析及其潜在靶基因的研究.海南医学院学报,2017, 23(6):732-735.] doi:10.13210/j.cnki.jhmu.20161229.006
[11]Pastuszak-Lewandoska D, Domanska-Senderowska D, Kordiak J, et al.Immunoexpression analysis of selected JAK/STAT pathway molecules in patients with non-small-cell lung cancer. Pol Arch Intern Med, 2017,127(11):758-764. doi:10.20452/pamw.4115
[12]Zhao JL, Sun XR, Ji DX, et al. Influence of STAT1 on proliferation and IFN-βsensitivity of human non-small-cell lung cancer H1299 cells. Chinese Journal of Pathophysiology, 2015, 31(5):852-856.[赵嘉璐,孙筱茹,季东翔,等.STAT1对人非小细胞肺癌H1299细胞增殖及IFN-β敏感性的影响.中国病理生理杂志,2015,31(5):852-856.]doi:10.3969/j.issn.1000-4718.2015.05.015
[13]Ma Y, Chen JJ, Chen CS, et al. Effect of STAT1 gene transfection on human lung carcinoma xenograft growth in nude mice. Wenzhou Yi Xue Yuan Xue Bao, 2013, 43(7):461-463.[马源,陈俊杰,陈成水,等.STAT1基因转染对人肺腺癌裸鼠移植瘤生长的影响.温州医学院学报,2013, 43(7):461-463.] doi:10.3969/j.issn.1000-2138.2013.07.010
[14]Wu P, Wu D, Zhao L, et al. Prognostic role of STAT3 in solid tumors:a systematic review and meta-analysis. Oncotarget, 2016, 7(15):19863-19883.doi:10.18632/oncotarget.7887
[15]Xu YH, Lu S. A meta-analysis of STAT3 and phospho-STAT3 expression and survival of patients with non-small-cell lung cancer. Eur J Surg Oncol,2014,40(3):311-317. doi:10.1016/j.ejso.2013.11.012
[16]Tong M, Wang J, Jiang N, et al. Correlation between p-STAT3overexpression and prognosis in lung cancer:A systematic review and meta-analysis. PLoS One, 2017, 12(8):e0182282. doi:10.1371/journal.pone.0182282
[17]Grabner B, Schramek D, Mueller KM, et al. Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis. Nat Commun, 2015, 6:6285.doi:10.1038/ncomms7285
[18]Jiang R, Jin Z, Liu Z, et al. Correlation of activated STAT3 expression with clinicopathologic features in lung adenocarcinoma and squamous cell carcinoma. Mol Diagn Ther, 2011, 15(6):347-352. doi:10.2165/11599190-000000000-00000
[19]Sun Y, Han Y, Wang X, et al. Correlation of EGFR Del 19 with Fn14/JAK/STAT signaling molecules in non-small cell lung cancer. Oncol Rep, 2016,36(2):1030-1040. doi:10.3892/or.2016.4905
[20]Chuang CH, Greenside PG, Rogers ZN, et al. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med, 2017, 23(3):291-300. doi:10.1038/nm.4285
[21]Lin HY, Chiang CH, Hung WC. STAT3 upregulates miR-92a to inhibit RECK expression and to promote invasiveness of lung cancer cells. Br J Cancer, 2013, 109(3):731-738. doi:10.1038/bjc.2013.349
[22]Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA, 2014,311(19):1998-2006. doi:10.1001/jama.2014.3741
[23]Bivona TG, Doebele RC. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med, 2016, 22(5):472-478. doi:10.1038/nm.4091
[24]Yao Z, Fenoglio S, Gao DC, et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci U S A, 2010, 107(35):15535-15540. doi:10.1073/pnas. 1009472107
[25]Kim SM, Kwon OJ, Hong YK, et al. Activation of IL-6R/JAK1/STAT3signaling induces de novo resistance to irreversible EGFR inhibitors in nonsmall cell lung cancer with T790M resistance mutation. Mol Cancer Ther,2012,11(10):2254-2264. doi:10.1158/1535-7163.MCT-12-0311
[26]Gao SP, Chang Q, Mao N, et al. JAK2 inhibition sensitizes resistant EGFRmutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal, 2016,9(421):ra33. doi:10.1126/scisignal.aac8460
[27]Chiu HC, Chou DL, Huang CT,et al. Suppression of Stat3 activity sensitizes gefitinib-resistant non small cell lung cancer cells. Biochem Pharmacol,2011,81(11):1263-1270. doi:10.1016/j.bcp.2011.03.003
[28]Blakely CM, Pazarentzos E, Olivas V, et al. NF-KB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep, 2015, 11(1):98-110. doi:10.1016/j.celrep.2015.03.012
[29]Lee HJ, Zhuang G, Cao Y, et al. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell, 2014, 26(2):207-221.doi:10.1016/j.ccr.2014.05.019
[30]Yu HA, Perez L, Chang Q, et al. A Phase 1/2 trial of ruxolitinib and erlotinib in patients with EGFR-mutant lung adenocarcinomas with acquired resistance to erlotinib. J Thorac Oncol, 2017,12(1):102-109. doi:10.1016/j.jtho.2016.08.140
[31]Leroy E, Constantinescu SN. Rethinking JAK2 inhibition:towards novelstrategies of more specific and versatile janus kinase inhibition. Leukemia,2017,31(5):1023-1038. doi:10.1038/leu.2017.43
[32]Tavallai M, Booth L, Roberts JL, et al. Rationally repurposing ruxolitinib(Jakafi((?)))as a solid tumor therapeutic. Front Oncol, 2016, 6:142. doi:10.3389/fonc.2016.00142
[33]Hu Y, Hong Y, Xu Y, et al. Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC. Apoptosis, 2014, 19(11):1627-1636. doi:10.1007/s10495-014-1030-z
[34]Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell, 2009,16(6):487-497. doi:10.1016/j.ccr.2009.10.015
[35]Xin H, Herrmann A, Reckamp K, et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res, 2011, 71(21):6601-6610.doi:10.1158/0008-5472.CAN-11-1217
[36]Lee JH, Park KS, Alberobello AT, et al. The Janus kinases inhibitor AZD 1480attenuates growth of small cell lung cancers in vitro and in vivo. Clin Cancer Res, 2013,19(24):6777-6786. doi:10.1158/1078-0432.CCR-13-1110
[37]Murakami T, Takigawa N, Ninomiya T, et al. Effect of AZD 1480 in an epidermal growth factor receptor-driven lung cancer model. Lung Cancer,2014,83(1):30-36. doi:10.1016/j.lungcan.2013.10.011
[38]Plimack ER, Lorusso PM, McCoon P, et al. AZD 1480:a phase I study of a novel JAK2 inhibitor in solid tumors. Oncologist, 2013, 18(7):819-820.doi:10.1634/theoncologist.2013-0198
[39]Kamran MZ, Patil P, Shirsath K, et al. Tyrosine kinase inhibitor AG490inhibits the proliferation and migration and disrupts actin organization of cancer cells. J Environ Pathol Toxicol Oncol, 2013, 32(4):361-371. doi:10.1615/JEnvironPatholToxicolO ncol.2013010051
[40]Zhao M, Liu F, Wang JY, et al. Effects of JAK2/STAT3 signaling pathway on angiogenesis in non-small cell lung cancer. Zhonghua Yi Xue Za Zhi,2011(6):375-381.[赵美,刘峰,王炯轶,等,JAK2/STAT3信号通路对非小细胞肺癌血管生成的影响.中华医学杂志,2011(6):375-381.] doi:10.3760/cma.j.issn.0376-2491.2011.06.004
[41]Liu RY, Zeng Y, Lei Z, et al. JAK/STAT3 signaling is required for TGF-β-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol,2014, 44(5):1643-1651.doi:10.3892/ijo.2014.2310
[42]Zhang X, Yue P, Page BD, et al. Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts. Proc Natl Acad Sci U S A, 2012, 109(24):9623-9628. doi:10.1073/pnas.1121606109
[43]JSM R, Aminudin N, Abd MSN. Chalepin:A compound from ruta angustifolia L. pers exhibits cell cycle arrest at S phase, suppresses nuclear factor-kappa B(NF-κB)pathway, signal transducer and activation of transcription 3(STAT3)phosphorylation and extrinsic apoptotic pathway in non-small cell lung cancer carcinoma(A549). Pharmacogn Mag, 2017,13(Suppl 3):S489-S498. doi:10.4103/pm.pm_13_17
[44]Blaskovich MA, Sun J, Cantor A, et al. Discovery of JSI-124(cucurbitacinⅠ), a selective Janus kinase/signal transducer and activator of transcription3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice. Cancer Res, 2003, 63(6):1270-1279.
[45]Guo H, Kuang S, Song QL, et al. Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments. Acta Pharmacol Sin, 2018, 39(3):425-437. doi:10.1038/aps.2017.99
[46]Wong AL, Soo RA, Tan DS, et al. PhaseⅠand biomarker study of OPB-51602, a novel signal transducer and activator of transcription(STAT)3 inhibitor, in patients with refractory solid malignancies. Ann Oncol, 2015,26(5):998-1005. doi:10.1093/annonc/mdv026
[47]Pfeiffer M, Hartmann T N, Leick M, et al. Alternative implication of CXCR4in JAK2/STAT3 activation in small cell lung cancer. British journal of cancer, 2009, 100(12):1949. doi:10.1038/sj.bjc.6605068
[48]Harada D, Takigawa N, Ochi N, et al. JAK 2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. Cancer science, 2012, 103(10):1795-1802. doi:10.1111/j.1349-7006.2012.02363.x