The DOI matches its Crossref record; 39 of the 40 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
In the citing paper
“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]
Citations
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
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829
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
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
MET 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
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
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
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
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
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
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
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
Wen, Z., Zhong, Z., & Darnell, J. E. (1995) · Cell · doi:10.1016/0092-8674(95)90311-9 · Cited by 1,974
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
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
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 1,270
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 1,177
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
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
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
Bromberg, J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15617 · Cited by 863
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
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 791
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
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
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
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 479
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 451
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 337
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 262
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 252
Haber, D. A., Gray, N. S., & Baselga, J. M. (2011) · Cell · doi:10.1016/j.cell.2011.03.026 · Cited by 219
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 204
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
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 121
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 101
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
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 84
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
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
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 3,191
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
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 997
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 728
Metadata
- 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
- Life Sciences › Immunology and Microbiology › Immunology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review