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FGFR leads to sustained activation of STAT3 to mediate resistance to EGFR-TKIs treatment

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Summary

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to great advances in the treatment of non-small cell lung cancer (NSCLC), but the emergence of drug resistance severely limits their clinical use. Thus, elucidation of the mechanism underlying resistance to EGFR-TKIs is of great importance. In our study, sustained activation of STAT3 was confirmed to be involved in resistance to EGFR-TKIs, and this resistance occurred regardless of exposure time, EGFR-TKIs type, and even cancer cell type. Mechanistically, the sustained activation of STAT3 was not related to gp130/JAK signalling pathway or HER2/EGFR heterodimer formation, while related to the expression and activation levels of STAT3. Furthermore, FGFR was shown to bind more strongly to STAT3 after gefitinib treatment, and the inhibition of FGFR reduced the phosphorylation of STAT3, thereby counteracting the effects of EGFR-TKIs and resulting in the synergistic inhibition of cancer cell proliferation. Taken together, the FGFR/STAT3 axis mediates the sustained activation of STAT3 upon EGFR-TKI treatment. This finding elucidates a new mechanism underlying drug resistance to EGFR-TKIs that the FGFR/STAT3 axis mediates the sustained activation of STAT3, providing theoretical support for considering the combination of TKIs and FGFR inhibitors in clinical cancer treatment.

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All data generated or analysed during this study are included in this published article.

References

  1. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29:2866–2874. https://doi.org/10.1200/JCO.2010.33.4235

    Article  CAS  PubMed  Google Scholar 

  2. Thongprasert S, Duffield E, Saijo N, Wu YL, Yang JC, Chu DT, Liao M, Chen YM, Kuo HP, Negoro S, Lam KC, Armour A, Magill P, Fukuoka M (2011) Health-related quality-of-life in a randomized phase III first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients from Asia with advanced NSCLC (IPASS) J Thorac Oncol 6:1872–1880. https://doi.org/10.1097/JTO.0b013e31822adaf7

    Article  PubMed  Google Scholar 

  3. Song X, Qi X, Wang Q, Zhu W, Li J (2017) A novel multi-target inhibitor harboring selectivity of inhibiting EGFR T790M sparing wild-type EGFR. Am J Cancer Res 7:1884-1898

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W (2014) AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 4:1046–1061. https://doi.org/10.1158/2159-8290.CD-14-0337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wu K, Chang Q, Lu Y, Qiu P, Chen B, Thakur C, Sun J, Li L, Kowluru A, Chen F (2013) Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells. Oncotarget 4:2430–2438. https://doi.org/10.18632/oncotarget.1431

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 15:440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947

    Article  CAS  Google Scholar 

  7. Codony-Servat C, Codony-Servat J, Karachaliou N, Molina MA, Chaib I, Ramirez JL, de Los Llanos Gil M, Solca F, Bivona TG, Rosell R (2017) Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC). Oncotarget 18:47305–47316. https://doi.org/10.18632/oncotarget.17625

    Article  Google Scholar 

  8. Zhao C, Li H, Lin HJ, Yang S, Lin J, Liang G (2016) Feedback activation of STAT3 as a cancer drug-resistance mechanism. Trends Pharmacol Sci 37:47–61. https://doi.org/10.1016/j.tips.2015.10.001

    Article  CAS  PubMed  Google Scholar 

  9. Alvarez JV, Greulich H, Sellers WR, Meyerson M, Frank DA (2006) Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Res 66:3162–3168. https://doi.org/10.1158/0008-5472.CAN-05-3757

    Article  CAS  PubMed  Google Scholar 

  10. Greulich H, Chen TH, Feng W, Jänne PA, Alvarez JV, Zappaterra M, Bulmer SE, Frank DA, Hahn WC, Sellers WR, Meyerson M (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313. https://doi.org/10.1371/journal.pmed.0020313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Song L, Rawal B, Nemeth JA, Haura EB (2011) JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol Cancer Ther 10:481–494. https://doi.org/10.1158/1535-7163.MCT-10-0502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun J, Blaskovich MA, Jove R, Livingston SK, Coppola D, Sebti SM (2005) Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. Oncogene 24:3236–3245. https://doi.org/10.1038/sj.onc.1208470

    Article  CAS  PubMed  Google Scholar 

  13. Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik CM, Xin H, Armstrong B, Bebernitz G, Weng S, Wang L, Ye M, McEachern K, Chen H, Morosini D, Bell K, Alimzhanov M, Ioannidis S, McCoon P, Cao ZA, Yu H, Jove R, Zinda M (2009) The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell 16:487–497. https://doi.org/10.1016/j.ccr.2009.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang Y, van Boxel-Dezaire AH, Cheon H, Yang J, Stark GR (2013) STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor. Proc Natl Acad Sci U S A 110:16975–16980. https://doi.org/10.1073/pnas.1315862110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, Begley CG (2002) An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene 21:460–474. https://doi.org/10.1038/sj.onc.1205100

    Article  CAS  PubMed  Google Scholar 

  16. Arcila ME, Nafa K, Chaft JE, Rekhtman N, Lau C, Reva BA, Zakowski MF, Kris MG, Ladanyi M (2013) EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther 12:220–229. https://doi.org/10.1158/1535-7163.MCT-12-0620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hart KC, Robertson SC, Kanemitsu MY, Meyer AN, Tynan JA, Donoghue DJ (2000) Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19:3309–3320. https://doi.org/10.1038/sj.onc.1203650

    Article  CAS  PubMed  Google Scholar 

  18. Ware KE, Marshall ME, Heasley LR, Marek L, Hinz TK, Hercule P, Helfrich BA, Doebele RC, Heasley LE (2010) Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One 5:e14117. https://doi.org/10.1371/journal.pone.0014117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sharma SV, Settleman J (2007) Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev 21:3214–3231. https://doi.org/10.1101/gad.1609907

    Article  CAS  PubMed  Google Scholar 

  20. Xu AM, Huang PH (2010) Receptor tyrosine kinase coactivation networks in cancer. Cancer Res 70:3857–3860. https://doi.org/10.1158/0008-5472.CAN-10-0163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao SP, Chang Q, Mao N, Daly LA, Vogel R, Chan T, Liu SH, Bournazou E, Schori E, Zhang H, Brewer MR, Pao W, Morris L, Ladanyi M, Arcila M, Manova-Todorova K, de Stanchina E, Norton L, Levine RL, Altan-Bonnet G, Solit D, Zinda M, Huszar D, Lyden D, Bromberg JF (2016) JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors. Sci Signal 9:ra33. https://doi.org/10.1126/scisignal.aac8460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim HP, Han SW, Kim SH, Im SA, Oh DY, Bang YJ, Kim TY (2008) Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells. Mol Cancer Ther 7:607–615. https://doi.org/10.1158/1535-7163.MCT-07-2068

    Article  CAS  PubMed  Google Scholar 

  23. Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J (2014) Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26:207–221. https://doi.org/10.1016/j.ccr.2014.05.019

    Article  CAS  PubMed  Google Scholar 

  24. Ochi N, Takigawa N, Harada D, Yasugi M, Ichihara E, Hotta K, Tabata M, Tanimoto M, Kiura K (2014) Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. Exp Cell Res 322:168–177. https://doi.org/10.1016/j.yexcr.2014.01.007

    Article  CAS  PubMed  Google Scholar 

  25. Noro R, Gemma A, Kosaihira S, Kokubo Y, Chen M, Seike M, Kataoka K, Matsuda K, Okano T, Minegishi Y, Yoshimura A, Kudoh S (2006) Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation. BMC Cancer 6:277. https://doi.org/10.1186/1471-2407-6-277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We appreciate Dr. Heidi Greulich’s generous help for providing the plasmids (EGFR D770-N771 insNPG, gag/pol and VSV-G).

Funding

This work was supported by the National Natural Science Foundation of China [No. 81673450] and the NSFC Shandong Joint Fund [U1606403, U1906212]; the Scientific and Technological Innovation Project was financially supported by Qingdao National Laboratory for Marine Science and Technology [No. 2015ASKJ02], the National Science and Technology Major Project for Significant New Drugs Development (2018ZX09735-004),Shandong Provincial Natural Science Foundation (major basic research projects, ZR2019ZD18) and Scientific Research Program Funded by Shaanxi Provincial Education Department (Program No. 19JK0850).

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Authors and Affiliations

  1. Key Laboratory of Marine Drugs, School of Medicine and Pharmacy, Chinese Ministry of Education, Ocean University of China, Qingdao, 266100, People’s Republic of China

    Xiaoping Song, Wei Tang, Hui Peng, Xin Qi & Jing Li

  2. Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, People’s Republic of China

    Xiaoping Song & Jing Li

  3. Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 North Taibai Road, Xi’an, 710069, People’s Republic of China

    Xiaoping Song

  4. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, People’s Republic of China

    Jing Li

  5. School of Medicine and Pharmacy, Ocean University of China, Yushan Road, Shinan District, 2tivation of STAT3 me6003, Qingdao, Shandong, 266003, People’s Republic of China

    Jing Li

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  1. Xiaoping Song
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Xiaoping Song, Wei Tang, Hui Peng, Xin Qi. The first draft of the manuscript was written by Xiaoping Song and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jing Li.

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Song, X., Tang, W., Peng, H. et al. FGFR leads to sustained activation of STAT3 to mediate resistance to EGFR-TKIs treatment. Invest New Drugs 39, 1201–1212 (2021). https://doi.org/10.1007/s10637-021-01061-1

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  • DOI: https://doi.org/10.1007/s10637-021-01061-1

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