Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells
Open accessAbstract
Pathway-targeted cancer drugs can produce dramatic responses that are invariably limited by the emergence of drug-resistant cells. We found that many drug-treated "oncogene-addicted" cancer cells engage a positive feedback loop leading to Stat3 activation, consequently promoting cell survival and limiting overall drug response. This was observed in cancer cells driven by diverse activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. Specifically, MEK inhibition led to autocrine activation of Stat3 via the FGF receptor and JAK kinases, and pharmacological inhibition of MEK together with JAK and FGFR enhanced tumor regression. These findings suggest that inhibition of a Stat3 feedback loop may augment the response to a broad spectrum of drugs that target pathways of oncogene addiction.
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Lee et al. found that transient STAT3 activation mediated by IL-6 and FGFR in response to oncogenic kinase inhibition significantly contributes to survival of several different oncogene-addicted cancer cell lines.
“Lee et al. found that transient STAT3 activation mediated by IL-6 and FGFR in response to oncogenic kinase inhibition significantly contributes to survival of several different oncogene-addicted cancer cell lines [67].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [67]
Many oncogene-addicted cancer cells (including EGFR, HER2, ALK, MET, KRAS) engage an IL-6 dependent feedback loop leading to STAT3 activation, which promotes cell survival and limits the overall drug response.
“Similarly, Lee et al., found that many oncogene-addicted cancer cells (including EGFR, HER2, ALK, MET, KRAS) engage an IL-6 dependent feedback loop leading to STAT3 activation [67]. This STAT3 activation promotes cell survival and limits the overall drug response.”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [67]
Cites
Differential expression analysis for sequence count data
Anders, S., & Huber, W. (2010) · Genome Biology · doi:10.1186/gb-2010-11-10-r106 · Cited by 15,581 · see citing works
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829 · see citing works
Glioma stem cells promote radioresistance by preferential activation of the DNA damage response
Bao, S., Wu, Q., McLendon, R. E., Hao, Y., Shi, Q., Hjelmeland, A. B., Dewhirst, M. W., Bigner, D. D., & Rich, J. N. (2006) · Nature · doi:10.1038/nature05236 · Cited by 6,363 · see citing works
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681 · see citing works
<i>MET</i> Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496 · see citing works
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383 · see citing works
Györffy, B., Lanczky, A., Eklund, A. C., Denkert, C., Budczies, J., Li, Q., & Szallasi, Z. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0674-9 · Cited by 4,169 · see citing works
Epidermal growth factor receptor mutations in lung cancer
Sharma, S. V., Bell, D. W., Settleman, J., & Haber, D. A. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2088 · Cited by 3,170 · see citing works
Self-citationBromberg, J. F., Wrzeszczynska, M. H., Devgan, G., Zhao, Y., Pestell, R. G., Albanese, C., & Darnell, J. E. (1999) · Cell · doi:10.1016/s0092-8674(00)81959-5 · Cited by 2,790 · see citing works
A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations
Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., McDermott, U., Azizian, N., Zou, L., Fischbach, M. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.02.027 · Cited by 2,770 · see citing works
Self-citationEMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer
Singh, A., & Settleman, J. (2010) · Oncogene · doi:10.1038/onc.2010.215 · Cited by 2,545 · see citing works
Self-citationUnresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., & Bernards, R. (2012) · Nature · doi:10.1038/nature10868 · Cited by 2,051 · see citing works
Wen, Z., Zhong, Z., & Darnell, J. E. (1995) · Cell · doi:10.1016/0092-8674(95)90311-9 · Cited by 1,974 · see citing works
Fast and SNP-tolerant detection of complex variants and splicing in short reads
Wu, T. D., & Nacu, S. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq057 · Cited by 1,894 · see citing works
Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., et al. (2012) · Nature · doi:10.1038/nature11183 · Cited by 1,771 · see citing works
O’Hare, T., Shakespeare, W. C., Zhu, X., Eide, C. A., Rivera, V. M., Wang, F., Adrian, L. T., Zhou, T., Huang, W.-S., Xu, Q., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.028 · Cited by 1,268 · see citing works
Roesch, A., Fukunaga‐Kalabis, M., Schmidt, E. C., Zabierowski, S. E., Brafford, P. A., Vultur, A., Basu, D., Gimotty, P. A., VOGT, T. M., & Herlyn, M. (2010) · Cell · doi:10.1016/j.cell.2010.04.020 · Cited by 1,162 · see citing works
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., et al. (2012) · Nature · doi:10.1038/nature11249 · Cited by 1,134 · see citing works
Self-citationAKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
Chandarlapaty, S., Sawai, A., Scaltriti, M., Rodrik-Outmezguine, V., Grbovic-Huezo, O., Serra, V., Majumder, P. K., Baselga, J., & Rosen, N. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.10.031 · Cited by 967 · see citing works
Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy
Huang, Q., Li, F., Liu, X., Li, W., Shi, W., Liu, F.-F., O'Sullivan, B., He, Z., Peng, Y., Tan, A.-C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2385 · Cited by 886 · see citing works
Bromberg, J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15617 · Cited by 846 · see citing works
Shuai, K., Horvath, C. M., Huang, L. H. T., Qureshi, S. A., Cowburn, D., & Darnell, J. E. (1994) · Cell · doi:10.1016/0092-8674(94)90357-3 · Cited by 807 · see citing works
Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia
Rajala, H. L. M., Eldfors, S., Ellonen, P., van Adrichem, A. J., Kuusanmäki, H. A., Andersson, E. I., Lagström, S., Clemente, M. J., Olson, T. L., Jalkanen, S. E., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1114885 · Cited by 775 · see citing works
Duncan, J. S., Whittle, M. C., Nakamura, K., Abell, A. N., Midland, A. A., Zawistowski, J. S., Johnson, N. L., Granger, D. A., Jordan, N. V., Darr, D. B., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.053 · Cited by 732 · see citing works
Tumor adaptation and resistance to RAF inhibitors
Lito, P., Rosen, N., & Solit, D. B. (2013) · Nature Medicine · doi:10.1038/nm.3392 · Cited by 585 · see citing works
Sos, M. L., Koker, M., Weir, B. A., Heynck, S., Rabinovsky, R., Zander, T., Seeger, J. M., Weiss, J., Fischer, F., Frommolt, P., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4055 · Cited by 504 · see citing works
Wang, S. E., Narasanna, A., Pérez-Torres, M., Xiang, B., Wu, F. Y., Yang, S., Carpenter, G. F., Gazdar, A. F., Muthuswamy, S. K., & Arteaga, C. L. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.05.023 · Cited by 474 · see citing works
Oncogene addiction: setting the stage for molecularly targeted cancer therapyPreprint
Sharma, S. V., & Settleman, J. E. (2007) · Genes & Development · doi:10.1101/gad.1609907 · Cited by 442 · see citing works
Self-citationStrategies to overcome resistance to targeted protein kinase inhibitors
Daub, H., Specht, K., & Ullrich, A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1579 · Cited by 333 · see citing works
Guryanova, O. A., Wu, Q., Cheng, L., Lathia, J. D., Huang, Z., Yang, J. B., MacSwords, J., Eyler, C. E., McLendon, R. E., Heddleston, J. M., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.004 · Cited by 259 · see citing works
Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas
Pilati, C., Amessou, M., Bihl, M., Balabaud, C. P., Nhieu, J. T. V., Paradis, V., Nault, J., Izard, T., Bioulac‐Sage, P., Couchy, G., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20110283 · Cited by 242 · see citing works
Haber, D. A., Gray, N. S., & Baselga, J. M. (2011) · Cell · doi:10.1016/j.cell.2011.03.026 · Cited by 215 · see citing works
STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers
Wang, X., Crowe, P. J., Goldstein, D., & Yang, J. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1568 · Cited by 202 · see citing works
Kim, S. M., Kwon, O.-J., Hong, Y. K., Kim, J. H., Solca, F., Ha, S., Soo, R. A., Christensen, J. G., Lee, J. H., & Cho, B. C. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0311 · Cited by 202 · see citing works
Yonesaka, K., Zejnullahu, K., Lindeman, N. I., Homes, A. J., Jackman, D. M., Zhao, F., Rogers, A. M., Johnson, B. E., & Janne, P. A. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0957 · Cited by 120 · see citing works
MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines
Vultur, A., Villanueva, J., Krepler, C., Rajan, G., Chen, Q., Xiao, M., Li, L., Gimotty, P. A., Wilson, M. A., Hayden, J., et al. (2013) · Oncogene · doi:10.1038/onc.2013.131 · Cited by 100 · see citing works
Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Lee, H.-J., Schaefer, G., Heffron, T. P., Shao, L., Ye, X., Sideris, S., Malek, S., Chan, E., Merchant, M., La, H., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0357 · Cited by 90 · see citing works
Self-citationHutti, J. E., Pfefferle, A. D., Russell, S. C., Sircar, M., Perou, C. M., & Baldwin, A. S. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-4141 · Cited by 81 · see citing works
From regulation of dying cell engulfment to development of anti-cancer therapy
Krysko, D. V., & Vandenabeele, P. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402271 · Cited by 71 · see citing works
Flagged first, then by citations
1 of the 40 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Targeting the IL-6/JAK/STAT3 signalling axis in cancer
Johnson, D. E., O'Keefe, R. A., & Grandis, J. R. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.8 · Cited by 3,110 · see citing works
Emerging Biological Principles of Metastasis
Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017) · Cell · doi:10.1016/j.cell.2016.11.037 · Cited by 3,075 · see citing works
Hata, A. N., Niederst, M. J., Archibald, H. L., Gomez-Caraballo, M., Siddiqui, F. M., Mulvey, H. E., Maruvka, Y. E., Ji, F., Bhang, H.-E. C., Krishnamurthy Radhakrishna, V., et al. (2016) · Nature Medicine · doi:10.1038/nm.4040 · Cited by 985 · see citing works
Understanding and targeting resistance mechanisms in NSCLC
Rotow, J. K., & Bivona, T. G. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.84 · Cited by 978 · see citing works
JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression
Owen, K. L., Brockwell, N. K., & Parker, B. S. (2019) · Cancers · doi:10.3390/cancers11122002 · Cited by 711 · see citing works
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606 · see citing works
Emran, T. B., Shahriar, A., Mahmud, A. R., Rahman, T., Abir, M. H., Siddiquee, M. F. R., Ahmed, H., Rahman, N., Nainu, F., Wahyudin, E., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891652 · Cited by 606 · see citing works
Overcoming therapy resistance in EGFR-mutant lung cancer
Passaro, A., Jänne, P. A., Mok, T., & Peters, S. (2021) · Nature Cancer · doi:10.1038/s43018-021-00195-8 · Cited by 565 · see citing works
Kemp, J. A., Shim, M. S., Heo, C. Y., & Kwon, Y. J. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.10.019 · Cited by 508 · see citing works
Therapy-induced tumour secretomes promote resistance and tumour progression
Obenauf, A. C., Zou, Y., Ji, A. L., Vanharanta, S., Shu, W., Shi, H., Kong, X., Bosenberg, M., Wiesner, T., Rosen, N. X., et al. (2015) · Nature · doi:10.1038/nature14336 · Cited by 485 · see citing works
Hong, D., Kurzrock, R., Kim, Y., Woessner, R., Younes, A., Nemunaitis, J., Fowler, N., Zhou, T., Schmidt, J., Jo, M., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aac5272 · Cited by 445 · see citing works
The potential and controversy of targeting STAT family members in cancer
Verhoeven, Y., Tilborghs, S., Jacobs, J., De Waele, J., Quatannens, D., Deben, C., Prenen, H., Pauwels, P., Trinh, X. B., Wouters, A., et al. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.10.002 · Cited by 409 · see citing works
A combinatorial strategy for treating KRAS-mutant lung cancer
Manchado, E., Weissmueller, S., Morris, J. P., Chen, C.-C., Wullenkord, R., Lujambio, A., de Stanchina, E., Poirier, J. T., Gainor, J. F., Corcoran, R. B., et al. (2016) · Nature · doi:10.1038/nature18600 · Cited by 403 · see citing works
Kartikasari, A. E. R., Huertas, C. S., Mitchell, A., & Plebanski, M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.692142 · Cited by 343 · see citing works
Castellanos, E. H., Feld, E., & Horn, L. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.12.014 · Cited by 319 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…STAT3 plays an important role in the tumor microenvironment, as it modulates antitumor immune response, where it plays dual and complementary roles as an upregulator of tumor immune inhibitors and a suppressor of tumor immune activators (Yu et al., 2007;Marzec et al., 2008; Lee et al., 2014).”
BackgroundGaudino, S. J., & Kumar, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00360 · Cited by 304 · see citing works
Jak Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition
Groner, B., & von Manstein, V. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.05.033 · Cited by 304 · see citing works
Chae, Y. K., Ranganath, K., Hammerman, P. S., Vaklavas, C., Mohindra, N. A., Kalyan, A., Matsangou, M., Costa, R. L. B., Carneiro, B. A., Villaflor, V. M., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.14109 · Cited by 299 · see citing works
Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery
Hu, Y., Dong, Z., & Liu, K. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-02949-5 · Cited by 288 · see citing works
Polytherapy and Targeted Cancer Drug Resistance
Chatterjee, N., & Bivona, T. G. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.02.003 · Cited by 271 · see citing works
Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure
Pagliarini, R. A., Shao, W., & Sellers, W. R. (2015) · EMBO Reports · doi:10.15252/embr.201439949 · Cited by 255 · see citing works
Targeting JAK kinase in solid tumors: emerging opportunities and challenges
Büchert, M., Burns, C. J., & Ernst, M. (2015) · Oncogene · doi:10.1038/onc.2015.150 · Cited by 241 · see citing works
Feedback Activation of STAT3 as a Cancer Drug-Resistance Mechanism
Zhao, C., Li, H., Lin, H.-J. L., Yang, S., Lin, J., & Liang, G. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.10.001 · Cited by 235 · see citing works
Yan, F., Al‐Kali, A., Zhang, Z. S., Liu, J., Pang, J., Zhao, N., He, C., Litzow, M. R., & Liu, S. (2018) · Cell Research · doi:10.1038/s41422-018-0097-4 · Cited by 235 · see citing works
Do STAT3 inhibitors have potential in the future for cancer therapy?
Wong, A. L. A., Hirpara, J. L., Pervaiz, S., Eu, J. Q., Sethi, G., & Goh, B.-C. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1351941 · Cited by 227 · see citing works
Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: Current status in clinical trials
Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y., & Wei, X. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.05.006 · Cited by 212 · see citing works
Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?
Szumilak, M., Wiktorowska‐Owczarek, A., & Stańczak, A. (2021) · Molecules · doi:10.3390/molecules26092601 · Cited by 212 · see citing works
Cancer drug-tolerant persister cells: from biological questions to clinical opportunities
Russo, M., Chen, M., Mariella, E., Peng, H., Rehman, S. K., Sancho, E., Sogari, A., Toh, T. S., Balaban, N. Q., Batlle, E., et al. (2024) · Nature Reviews Cancer · doi:10.1038/s41568-024-00737-z · Cited by 210 · see citing works
Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC
CHAIB-OUKADOUR, I., Karachaliou, N., Pilotto, S., Servat, J. C., Cai, X., Li, X., Drozdowskyj, A., Codony, C., Yang, J. E., Hu, C., et al. (2017) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djx014 · Cited by 210 · see citing works
Blakely, C. M., Pazarentzos, E., Olivas, V., Asthana, S., Yan, J. J., Tan, I., Hrustanovic, G., Chan, E., Lin, L., Neel, D. S., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.012 · Cited by 204 · see citing works
Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance
Cui, C., Yang, J., Xiao, L., Liu, D., Fu, L., & Wang, X. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01180-y · Cited by 204 · see citing works
Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)
Powell, C. E., Gao, Y., Tan, L., Donovan, K. A., Nowak, R. P., Loehr, A., Bahcall, M., Fischer, E. S., Jänne, P. A., George, R. E., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01655 · Cited by 198 · see citing works
Akbay, E. A., Koyama, S., Liu, Y., Dries, R., Bufe, L. E., Silkes, M., Alam, M. M., Magee, D. M., Jones, R. E., Jinushi, M., et al. (2017) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2017.04.017 · Cited by 199 · see citing works
Cytokines in cancer drug resistance: Cues to new therapeutic strategies
Jones, V. S., Huang, R.-Y., Chen, L.-P., Chen, Z., Fu, L., & Huang, R.-P. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.03.005 · Cited by 196 · see citing works
The JAK/STAT3 axis: A comprehensive drug target for solid malignancies
Huynh, J., Etemadi, N., Hollande, F., Ernst, M., & Büchert, M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.06.001 · Cited by 197 · see citing works
ALK-positive lung cancer: a moving target
Schneider, J. L., Lin, J. J., & Shaw, A. T. (2023) · Nature Cancer · doi:10.1038/s43018-023-00515-0 · Cited by 190 · see citing works
Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer
Cabanos, H. F., & Hata, A. N. (2021) · Cancers · doi:10.3390/cancers13112666 · Cited by 189 · see citing works
Tan, L., Wang, J., Tanizaki, J., Huang, Z., Aref, A. R., Rusan, M., Zhu, S.-J., Zhang, Y., Ercan, D., Liao, R. G., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1403438111 · Cited by 178 · see citing works
Thioredoxin Reductase Inhibition for Cancer Therapy
Gencheva, R., & Arnér, E. S. J. (2021) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-052220-102509 · Cited by 178 · see citing works
Survival of pancreatic cancer cells lacking KRAS function
Muzumdar, M. D., Chen, P.-Y., Dorans, K. J., Chung, K. M., Bhutkar, A., Hong, E., Noll, E. M., Sprick, M. R., Trumpp, A., & Jacks, T. (2017) · Nature Communications · doi:10.1038/s41467-017-00942-5 · Cited by 177 · see citing works
A framework for understanding and targeting residual disease in oncogene-driven solid cancers
Bivona, T. G., & Doebele, R. C. (2016) · Nature Medicine · doi:10.1038/nm.4091 · Cited by 176 · see citing works
Wong, A. L. A., Soo, R. A., Tan, D. S. W., Lee, S. C., Lim, J. S. J., Marban, P., Kong, L. R., Lee, Y. J., Wang, L. Z., Thuya, W. L., et al. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv026 · Cited by 175 · see citing works
Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development
Sgrignani, J., Garofalo, M., Matkovic, M., Merulla, J., Catapano, C. V., & Cavalli, A. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061591 · Cited by 166 · see citing works
Kitai, H., Ebi, H., Tomida, S., Floros, K. V., Kotani, H., Adachi, Y., Oizumi, S., Nishimura, M., Faber, A. C., & Yano, S. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1377 · Cited by 162 · see citing works
Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer
Jacobsen, K., Bertrán-Alamillo, J., Molina‐Vila, M. Á., Teixidó, C., Karachaliou, N., Pedersen, M. H., Castellví, J., Garzón, M., Codony, C., Codony‐Servat, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00450-6 · Cited by 159 · see citing works
Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy
Li, J., Eu, J. Q., Kong, L. R., Wang, L., Lim, Y. C., Goh, B. C., & Wong, A. L. (2020) · Molecules · doi:10.3390/molecules25204831 · Cited by 159 · see citing works
Surviving apoptosis: life–death signaling in single cells
Flusberg, D. A., & Sorger, P. K. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.03.003 · Cited by 149 · see citing works
Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis
Wu, P., Wu, D., Zhao, L., Huang, L., Shen, G., Huang, J., & Chai, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.7887 · Cited by 148 · see citing works
Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
Grabner, B., Schramek, D., Mueller, K. M., Moll, H. P., Svinka, J., Hoffmann, T., Bauer, E., Blaas, L., Hruschka, N., Zboray, K., et al. (2015) · Nature Communications · doi:10.1038/ncomms7285 · Cited by 143 · see citing works
Bhat, A. A., Nisar, S., Maacha, S., Carneiro-Lobo, T., Akhtar, S., Siveen, K. S., Wani, N. A., Rizwan, A., Bagga, P., Singh, M. K., et al. (2021) · Molecular Cancer · doi:10.1186/s12943-020-01294-3 · Cited by 143 · see citing works
Two decades of research in discovery of anticancer drugs targeting STAT3, how close are we?
Beebe, J., Liu, J., & Zhang, J. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.06.006 · Cited by 142 · see citing works
Garg, M., Shanmugam, M. K., Bhardwaj, V., Goel, A., Gupta, R., Sharma, A., Baligar, P., Kumar, A. P., Goh, B. C., Wang, L., et al. (2020) · Medicinal Research Reviews · doi:10.1002/med.21761 · Cited by 142 · see citing works
Mathematical modeling and computational prediction of cancer drug resistance
Sun, X., & Hu, B. X. (2017) · Briefings in Bioinformatics · doi:10.1093/bib/bbx065 · Cited by 141 · see citing works
Poli, V., & Camporeale, A. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00121 · Cited by 135 · see citing works
Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling
Junk, D. J., Bryson, B. L., Smigiel, J. M., Parameswaran, N., Bartel, C. A., & Jackson, M. W. (2017) · Oncogene · doi:10.1038/onc.2017.33 · Cited by 133 · see citing works
Kooshkaki, O., Derakhshani, A., Hosseinkhani, N., Torabi, M., Safaei, S., Brunetti, O., Racanelli, V., Silvestris, N., & Baradaran, B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124427 · Cited by 133 · see citing works
Sun, X., Bao, J., & Shao, Y. (2016) · Scientific Reports · doi:10.1038/srep22498 · Cited by 130 · see citing works
STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications
Tošić, I., & Frank, D. A. (2021) · Neoplasia · doi:10.1016/j.neo.2021.10.003 · Cited by 130 · see citing works
Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion
Jiang, H., Liu, X., Knolhoff, B. L., Hegde, S., Lee, K. B., Jiang, H., Fields, R. C., Pachter, J. A., Lim, K.-H., & DeNardo, D. G. (2020) · Gut · doi:10.1136/gutjnl-2018-317424 · Cited by 130 · see citing works
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Rusan, M., Li, K., Li, Y. Y., Christensen, C. L., Abraham, B. J., Kwiatkowski, N. P., Buczkowski, K. A., Bockorny, B., Chen, T., Li, S., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0461 · Cited by 128 · see citing works
Targeting STAT3 and oxidative phosphorylation in oncogene-addicted tumors
Lee, M., Hirpara, J. L., Eu, J. Q., Sethi, G., Wang, L., Goh, B.-C., & Wong, A. L. A. (2018) · Redox Biology · doi:10.1016/j.redox.2018.101073 · Cited by 128 · see citing works
Cheng, Y., Zhang, T., & Xu, Q. (2021) · MedComm · doi:10.1002/mco2.105 · Cited by 125 · see citing works
Hirpara, J. L., Eu, J. Q., Tan, J. K. M., Wong, A. L., Clement, M., Kong, L. R., Ohi, N., Tsunoda, T., Qu, J., Goh, B. C., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2018.101076 · Cited by 122 · see citing works
Ge, X., Liu, X., Lin, F., Li, P., Liu, K., Geng, R., Dai, C., Lin, Y., Tang, W., Wu, Z., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.8228 · Cited by 118 · see citing works
FGF/FGFR signaling pathway involved resistance in various cancer types.
Zhou, Y., Wu, C., Lu, G., Hu, Z., Chen, Q., & Du, X. (2020) · Journal of Cancer · doi:10.7150/jca.40531 · Cited by 117 · see citing works
A TNF–JNK–Axl–ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma
Guo, G., Gong, K., Ali, S., Ali, N., Shallwani, S., Hatanpaa, K. J., Pan, E., Mickey, B., Burma, S., Wang, D. H., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4584 · Cited by 114 · see citing works
Sui, H. X., Zhang, L., Gu, K., Chai, N., Ji, Q., Zhou, L., Wang, Y., Ren, J., Yang, L., Zhang, B., et al. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00596-9 · Cited by 112 · see citing works
Targeting STAT3 with silibinin to improve cancer therapeutics
Bosch‐Barrera, J., Queralt, B., & Menéndez, J. A. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.06.003 · Cited by 111 · see citing works
Shien, K., Papadimitrakopoulou, V. A., Ruder, D., Behrens, C., Shen, L., Kalhor, N., Song, J., Lee, J. J., Wang, J., Tang, X., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0148 · Cited by 109 · see citing works
IRF9 and unphosphorylated STAT2 cooperate with NF-κB to drive IL6 expression
Jing, N., Wang, Y., Yang, J. B., & Stark, G. R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1714102115 · Cited by 109 · see citing works
Emerging nanotechnology-based therapeutics to combat multidrug-resistant cancer
Yadav, P., Ambudkar, S. V., & Prasad, N. R. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01626-z · Cited by 109 · see citing works
Xiao, W., Song, M., Li, W., Huang, J., Yang, G. Y., & Wang, Y. (2021) · Theranostics · doi:10.7150/thno.59342 · Cited by 108 · see citing works
STAT3: Versatile Functions in Non-Small Cell Lung Cancer
Mohrherr, J., Uras, I. Z., Moll, H. P., & Casanova, E. (2020) · Cancers · doi:10.3390/cancers12051107 · Cited by 106 · see citing works
Terai, H., Kitajima, S., Potter, D. S., Matsui, Y., Quiceno, L. G., Chen, T., Kim, T. J., Rusan, M., Thai, T. C., Piccioni, F., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1904 · Cited by 105 · see citing works
Nuclear factor of activated T cells in cancer development and treatment
Shou, J., Jing, J., Xie, J., You, L., Zhao, J., Yao, J., Han, W., & Pan, H. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.03.005 · Cited by 104 · see citing works
Bottos, A., Gotthardt, D., Gill, J. W., Gattelli, A., Frei, A., Tzankov, A., Sexl, V., Wodnar‐Filipowicz, A., & Hynes, N. E. (2016) · Nature Communications · doi:10.1038/ncomms12258 · Cited by 103 · see citing works
Maryam, A., Mehmood, T., Zhang, H., Li, Y., Khan, M. N., & Ma, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-06535-y · Cited by 101 · see citing works
Piñeiro-Yáñez, E., Reboiro‐Jato, M., Goméz-López, G., Perales-Patón, J., Troulé, K., Rodrı́guez, J. M., Tejero, H., Shimamura, T., Lopez-Casas, P. P., Carretero, J., et al. (2018) · Genome Medicine · doi:10.1186/s13073-018-0546-1 · Cited by 101 · see citing works
Sabaawy, H. E., Ryan, B. M., Khiabanian, H., & Pine, S. R. (2021) · Carcinogenesis · doi:10.1093/carcin/bgab075 · Cited by 101 · see citing works
Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy
Santarpía, M., Liguori, A., Karachaliou, N., González‐Cao, M., Daffinà, M. G., D’Aveni, A., Marabello, G., Altavilla, G., & Rosell, R. (2017) · Lung Cancer Targets and Therapy · doi:10.2147/lctt.s119644 · Cited by 100 · see citing works
TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer
Gong, K., Guo, G., Gerber, D. E., Gao, B., Peyton, M., Huang, C., Minna, J. D., Hatanpaa, K. J., Kernstine, K., Cai, L., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96148 · Cited by 98 · see citing works
Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence
Sotto, A. D., Mancinelli, R., Gullì, M., Eufemi, M., Mammola, C. L., Mazzanti, G., & Giacomo, S. D. (2020) · Cancers · doi:10.3390/cancers12103034 · Cited by 97 · see citing works
Hanker, A. B., Garrett, J. T., Estrada, M. V., Moore, P. D., Ericsson, P. I. G., Koch, J. P., Langley, E. J., Singh, S., Kim, P. S., Frampton, G. M., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2287 · Cited by 96 · see citing works
Brambilla, L., Genini, D., Laurini, E., Merulla, J., Perez, L. H., Fermeglia, M., Carbone, G. M., Pricl, S., & Catapano, C. V. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.02.012 · Cited by 95 · see citing works
Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors by inhibiting STAT3 pathway
Yang, L., Lin, S., Kang, Y., Xiang, Y., Xu, L., Li, J., Dai, X., Liang, G., Huang, X., & Zhao, C. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-1015-9 · Cited by 94 · see citing works
Understanding the Genetic Mechanisms of Cancer Drug Resistance Using Genomic Approaches
Hu, X., & Zhang, Z. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.11.003 · Cited by 93 · see citing works
Gong, K., Guo, G., Panchani, N., Bender, M. E., Gerber, D. E., Minna, J. D., Fattah, F., Gao, B., Peyton, M., Kernstine, K., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0048-0 · Cited by 92 · see citing works
Addressing intra-tumoral heterogeneity and therapy resistance
Rybinski, B., & Yun, K. (2016) · Oncotarget · doi:10.18632/oncotarget.11875 · Cited by 92 · see citing works
Liang, Z., Wu, G., Fan, C., Xu, J., Jiang, S., Yan, X., Di, S., Ma, Z., Hu, W., & Yang, Y. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.11.001 · Cited by 92 · see citing works
Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma
Liu, J., Liu, Y., Meng, L., Liu, K., & Ji, B. (2017) · Oncology Reports · doi:10.3892/or.2017.5722 · Cited by 91 · see citing works
Calcium signaling in cancer progression and therapy
Wu, L., Lian, W., & Zhao, L. (2021) · FEBS Journal · doi:10.1111/febs.16133 · Cited by 91 · see citing works
Synthetic Lethal Vulnerabilities in <i>KRAS</i>-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90 · see citing works
Synthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
Sulahian, R., Kwon, J. J., Walsh, K. H., Pailler, E., Bosse, T. L., Thaker, M., Almanza, D., Dempster, J. M., Pan, J., Piccioni, F., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.090 · Cited by 90 · see citing works
Self-citationSun, C., Li, S., Zhang, F., Zhang, Y., Zuo, Z., Xi, Y., Wang, L., & Li, D. (2016) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2016.96 · Cited by 84 · see citing works
Targeting colon cancer with the novel STAT3 inhibitor bruceantinol
Wei, N., Li, J., Fang, C., Chang, J., Xirou, V., Syrigos, N. K., Marks, B. J., Chu, E., & Schmitz, J. C. (2018) · Oncogene · doi:10.1038/s41388-018-0547-y · Cited by 84 · see citing works
Underlying Causes and Therapeutic Targeting of the Inflammatory Tumor Microenvironment
Comen, E. A., Bowman, R. L., & Kleppe, M. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00056 · Cited by 84 · see citing works
InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma
Ma, Y., Tang, N., Thompson, R. C., Mobley, B. C., Clark, S. W., Sarkaria, J. N., & Wang, J. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1677 · Cited by 83 · see citing works
Inflammation as a driver and vulnerability of KRAS mediated oncogenesis
Kitajima, S., Thummalapalli, R., & Barbie, D. A. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.06.009 · Cited by 83 · see citing works
Activation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia
Soutto, M., Chen, Z., Bhat, A. A., Wang, L., Zhu, S., Gomaa, A. R., Bates, A. L., Bhat, N. S., Peng, D., Belkhiri, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11011-4 · Cited by 82 · see citing works
- Authors
- Lee, H.-J., Zhuang, G., Cao, Y., Du, P., Kim, H.-J., & Settleman, J.
- Affiliations
- Genentech (US)
- Corresponding author
- Settleman, Jeff
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 26
- Issue
- 2
- Pages
- 207-221
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2102365935
- Cited by
- 555
- References
- 40
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 36 · 2023: 41 · 2022: 38 · 2021: 61 · 2020: 55 · 2019: 63 · 2018: 46 · 2017: 65 · 2016: 54 · 2015: 42 · 2014: 4
- FWCI
- 26.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- STAT3, drug resistance, oncogene addiction, positive feedback loop, MEK inhibition, JAK inhibition, fibroblast growth factor receptor, EGFR, HER2, anaplastic lymphoma kinase, MET, mutant KRAS, autocrine signaling, combination therapy, tumor regression
- MeSH terms
- Erlotinib Hydrochloride, Adenocarcinoma of Lung, Adenocarcinoma, Animals, Antineoplastic Agents, Cell Survival, Humans, Imidazoles, Lung Neoplasms, Mutation, Nitriles, Oncogenes, Proto-Oncogene Proteins, Pyrazoles, Pyridazines, Pyrimidines, Quinazolines, Signal Transduction, Interleukin-6, Proto-Oncogene Proteins p21(ras), Mice, SCID, Receptors, Fibroblast Growth Factor, ras Proteins, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Kaplan-Meier Estimate, Janus Kinase 1, ErbB Receptors
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