TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer
Open accessAbstract
The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N'-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-beta-mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-beta-dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-beta are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.
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TGF-β induced expression of IL-6 and subsequent STAT3 activation could decrease erlotinib sensitivity.
“By studying erlotinib-resistant EGFR models that had undergone EMT, Yao et al. identified that TGF-β induced expression of IL-6 and subsequent STAT3 activation could decrease erlotinib sensitivity [89].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [89]
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Cites
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
Self-citation<i>EGFR</i> Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR
Maemondo, M., Inoue, A., Kobayashi, K., Sugawara, S., Oizumi, S., Isobe, H., Gemma, A., Harada, M., Yoshizawa, H., Kinoshita, I., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0909530 · Cited by 5,525 · 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
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338 · see citing works
Identification and expansion of the tumorigenic lung cancer stem cell population
Eramo, A., Lotti, F., Sette, G., Pilozzi, E., Biffoni, M., Virgilio, A. D., Conticello, C., Ruco, L., Peschle, C., & Maria, R. D. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402283 · Cited by 1,707 · see citing works
Catlett-Falcone, R., Landowski, T. H., Oshiro, M. M., Turkson, J., Levitzki, A., Savino, R., Ciliberto, G., Moscinski, L., Fernández-Luna, J. L., Nuñez, G., et al. (1999) · Immunity · doi:10.1016/s1074-7613(00)80011-4 · Cited by 1,638 · see citing works
Wakeling, A. E., Guy, S. P., Woodburn, J. R., Ashton, S. E., Curry, B. J., Barker, A. J., & Gibson, K. H. (2002) · PubMed · doi:10.7270/q2pc374f · Cited by 925 · see citing works
Engelman, J. A., & Janne, P. A. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-2248 · Cited by 706 · see citing works
Gao, S. P., Mark, K. G., Leslie, K., Pao, W., Motoi, N., Gerald, W. L., Travis, W. D., Bornmann, W., Veach, D., Clarkson, B., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31871 · Cited by 666 · see citing works
Thomson, S., Buck, E. A., Petti, F., Griffin, G., Brown, E., Ramnarine, N., Iwata, K. K., Gibson, N. W., & Haley, J. D. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1058 · Cited by 663 · see citing works
Inflammation and EMT: an alliance towards organ fibrosis and cancer progression
López-Novoa, J. M., & Nieto, M. A. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900043 · Cited by 655 · see citing works
Sequist, L. V. D., Bell, D. W., Lynch, T. J., & Haber, D. A. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.07.3585 · Cited by 617 · see citing works
Yauch, R. L., Januario, T., Eberhard, D. A., Cavet, G., Zhu, W., Fu, L., Pham, T. Q., Soriano, R., Stinson, J., Seshagiri, S., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1492 · Cited by 495 · see citing works
Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms
Haga, S., Terui, K., Zhang, H. Q., Enosawa, S., Ogawa, W., Inoue, H., Okuyama, T., Takeda, K., Akira, S., Ogino, T., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17970 · Cited by 237 · see citing works
Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms
Haga, S., Terui, K., Zhang, H. Q., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200317970 · Cited by 215 · see citing works
Gandhi, J., Zhang, J., Xie, Y., Soh, J., Shigematsu, H., Zhang, W., Yamamoto, H., Peyton, M., Girard, L., Lockwood, W. W., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004576 · Cited by 200 · see citing works
Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions
Barr, S. M., Thomson, S., Buck, E. A., Russo, S. M., Petti, F., Sujka-Kwok, I., Eyzaguirre, A., Rosenfeld-Franklin, M., Gibson, N. W., Miglarese, M. R., et al. (2008) · Clinical & Experimental Metastasis · doi:10.1007/s10585-007-9121-7 · Cited by 197 · see citing works
Involvement of lnterleukin-6 in the Elevation of Plasma Fibrinogen Levels in Lung Cancer Patients
Yamaguchi, T., Yamamoto, Y., Yokota, S., Nakagawa, M., Ito, M., & Ogura, T. (1998) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/28.12.740 · Cited by 80 · see citing works
The partition method for poset-free families
Griggs, J. R., & Li, W. (2012) · Journal of Combinatorial Optimization · doi:10.1007/s10878-012-9476-9 · Cited by 47 · see citing works
Induction of interleukin-6 in the epidermis of mice in response to tumor-promoting agents
Vasunia, K. B., Miller, M. L., Andringa, S., et al. (1994) · Carcinogenesis · doi:10.1093/carcin/15.8.1723 · Cited by 13 · see citing works
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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
Fischer, K. R., Durrans, A., Lee, S., Sheng, J., Li, F., Wong, S. T. C., Choi, H., El Rayes, T., Ryu, S., Troeger, J., et al. (2015) · Nature · doi:10.1038/nature15748 · Cited by 1,791 · see citing works
Self-citationCircumventing cancer drug resistance in the era of personalized medicine
Garraway, L. A., & Jänne, P. A. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0012 · Cited by 503 · see citing works
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor–Resistant Disease
Ohashi, K., Maruvka, Y. E., Michor, F., & Pao, W. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.3912 · Cited by 467 · see citing works
MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling
Huang, S., Hölzel, M., Knijnenburg, T., Schlicker, A., Roepman, P., McDermott, U., Garnett, M., Grernrum, W., Sun, C., Prahallad, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.035 · Cited by 430 · see citing works
Cancer associated fibroblasts: An essential role in the tumor microenvironment
Tao, L., Huang, G., Song, H., Chen, Y., & Chen, L. (2017) · Oncology Letters · doi:10.3892/ol.2017.6497 · Cited by 351 · see citing works
Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy
Kemper, K., de Goeje, P. L., Peeper, D. S., & van Amerongen, R. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1174 · Cited by 216 · 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
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
EGFR-mutated lung cancer: a paradigm of molecular oncology
Zhang, Z., Stiegler, A. L., Boggon, T. J., Kobayashi, S., & Halmos, B. (2010) · Oncotarget · doi:10.18632/oncotarget.186 · Cited by 197 · see citing works
Nilsson, M. B., Sun, H., Diao, L., Tong, P., Liu, D., Li, L., Fan, Y., Poteete, A., Lim, S.-O., Howells, K., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aao4307 · Cited by 146 · see citing works
TGF-β: An emerging player in drug resistance
Brunen, D., Willems, S., Kellner, U., Midgley, R., Simon, I., & Bernards, R. (2013) · Cell Cycle · doi:10.4161/cc.26034 · Cited by 124 · see citing works
Targeting tumour microenvironment by tyrosine kinase inhibitor
Tan, H.-Y., Wang, N., Lam, W., Guo, W., Feng, Y., & Cheng, Y.-C. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0800-6 · Cited by 107 · see citing works
Cell signaling and cancer: a mechanistic insight into drug resistance
Panda, M., & Biswal, B. K. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-04958-6 · Cited by 89 · see citing works
Nigro, A., Ricciardi, L., Salvato, I., Sabbatino, F., Vitale, M., Crescenzi, M. A., Montico, B., Triggiani, M., Pepe, S., Stellato, C., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2019.03135 · Cited by 70 · see citing works
Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling
Oh, H., Hwang, I., Jang, J.-Y., Wu, L., Cao, D., Yao, J., Ying, H., Li, J. Y., Yao, Y., Hu, B., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-1810 · Cited by 11 · see citing works
- Authors
- Yao, Z., Fenoglio, S., Gao, D. C., Camiolo, M., Stiles, B., Lindsted, T., Schlederer, M., Johns, C., Altorki, N., Mittal, V., Kenner, L., & Sordella, R.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Cornell University (US)
- Ludwig Boltzmann Institute for Cancer Research (AT)
- Houston Methodist (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-08-16
- Volume
- 107
- Issue
- 35
- Pages
- 15535-15540
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2932568
- OpenAlex
- W1982585264
- Cited by
- 389
- References
- 21
- Citations by year
- 2026: 7 · 2025: 22 · 2024: 12 · 2023: 20 · 2022: 11 · 2021: 20 · 2020: 25 · 2019: 32 · 2018: 25 · 2017: 33 · 2016: 21 · 2015: 33 · 2014: 39 · 2013: 32 · 2012: 32
- FWCI
- 23.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM008444)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- erlotinib resistance, EGFR tyrosine kinase inhibitors, non-small cell lung cancer, TGF-beta signaling, interleukin-6, epithelial-mesenchymal transition, acquired drug resistance, tumor microenvironment, inflammation, T790M mutation, MET amplification, adaptive resistance
- MeSH terms
- Erlotinib Hydrochloride, Gefitinib, Animals, Base Sequence, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Movement, Cell Survival, Epithelial Cells, Humans, Lung Neoplasms, Mesoderm, Mice, Nude, Mutation, Quinazolines, Interleukin-6, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, RNA Interference, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, ErbB Receptors
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