Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy

Oncogene volume 34, pages 1083–1093 (2015)Cite this article

Subjects

Abstract

Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Lee HE, Kim MA, Lee HS, Jung EJ, Yang HK, Lee BL et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer 2012; 107: 325–333.

    Article  CAS  Google Scholar 

  2. Garcia S, Dales JP, Charafe-Jauffret E, Carpentier-Meunier S, Andrac-Meyer L, Jacquemier J et al. Poor prognosis in breast carcinomas correlates with increased expression of targetable CD146 and c-Met and with proteomic basal-like phenotype. Hum Pathol 2007; 38: 830–841.

    Article  CAS  Google Scholar 

  3. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF . Met metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4: 915–925.

    Article  CAS  Google Scholar 

  4. Wickramasinghe D, Kong-Beltran M . Met activation and receptor dimerization in cancer: a role for the Sema domain. Cell Cycle (Georgetown, TX) 2005; 4: 683–685.

    Article  CAS  Google Scholar 

  5. Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR . Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci USA 2001; 98: 247–252.

    Article  CAS  Google Scholar 

  6. Nicholson KM, Anderson NG . The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002; 14: 381–395.

    Article  CAS  Google Scholar 

  7. Lee JM, Kim B, Lee SB, Jeong Y, Oh YM, Song YJ et al. Cbl-independent degradation of Met: ways to avoid agonism of bivalent Met-targeting antibody. Oncogene 2014; 33: 34–43.

    Article  CAS  Google Scholar 

  8. Landi L, Minuti G, D'Incecco A, Cappuzzo F . Targeting c-MET in the battle against advanced nonsmall-cell lung cancer. Curr Opin Oncol 2013; 25: 130–136.

    Article  CAS  Google Scholar 

  9. Scagliotti GV, Novello S, von Pawel J . The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev 2013; 39: 793–801.

    Article  CAS  Google Scholar 

  10. Cecchi F, Rabe DC, Bottaro DP . Targeting the HGF/Met signaling pathway in cancer therapy. Exp Opin Ther Targets 2012; 16: 553–572.

    Article  CAS  Google Scholar 

  11. Nagilla M, Brown RL, Cohen EE . Cabozantinib for the treatment of advanced medullary thyroid cancer. Adv Ther 2012; 29: 925–934.

    Article  CAS  Google Scholar 

  12. Basilico C, Pennacchietti S, Vigna E, Chiriaco C, Arena S, Bardelli A et al. Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET. Clin Cancer Res 2013; 19: 2381–2392.

    Article  CAS  Google Scholar 

  13. Sequist LV, von Pawel J, Garmey EG, Akerley WL, Brugger W, Ferrari D et al. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. J Clin Oncol 2011; 29: 3307–3315.

    Article  CAS  Google Scholar 

  14. Surati M, Patel P, Peterson A, Salgia R . Role of MetMAb (OA-5D5) in c-MET active lung malignancies. Exp Opin Biol Ther 2011; 11: 1655–1662.

    Article  CAS  Google Scholar 

  15. Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K et al. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol 2011; 29: 4803–4810.

    Article  CAS  Google Scholar 

  16. Ou SH, Kwak EL, Siwak-Tapp C, Dy J, Bergethon K, Clark JW et al. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J Thorac Oncol 2011; 6: 942–946.

    Article  Google Scholar 

  17. Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H et al. Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci USA 2006; 103: 2316–2321.

    Article  CAS  Google Scholar 

  18. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG . Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13: 714–726.

    Article  CAS  Google Scholar 

  19. Dechantsreiter MA, Planker E, Matha B, Lohof E, Holzemann G, Jonczyk A et al. N-methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 1999; 42: 3033–3040.

    Article  CAS  Google Scholar 

  20. Bachleitner-Hofmann T, Sun MY, Chen CT, Tang L, Song L, Zeng Z et al. HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells. Mol Cancer Ther 2008; 7: 3499–3508.

    Article  CAS  Google Scholar 

  21. Corso S, Ghiso E, Cepero V, Sierra JR, Migliore C, Bertotti A et al. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol Cancer 2010; 9: 121.

    Article  Google Scholar 

  22. Tiedt R, Degenkolbe E, Furet P, Appleton BA, Wagner S, Schoepfer J et al. A drug resistance screen using a selective MET inhibitor reveals a spectrum of mutations that partially overlap with activating mutations found in cancer patients. Cancer Res 2011; 71: 5255–5264.

    Article  CAS  Google Scholar 

  23. Cepero V, Sierra JR, Corso S, Ghiso E, Casorzo L, Perera T et al. MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res 2010; 70: 7580–7590.

    Article  CAS  Google Scholar 

  24. Lee NV, Lira ME, Pavlicek A, Ye J, Buckman D, Bagrodia S et al. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation. PLoS One 2012; 7: e39653.

    Article  CAS  Google Scholar 

  25. Fong JT, Jacobs RJ, Moravec DN, Uppada SB, Botting GM, Nlend M et al. Alternative signaling pathways as potential therapeutic targets for overcoming EGFR and c-Met inhibitor resistance in non-small cell lung cancer. PLoS One 2013; 8: e78398.

    Article  CAS  Google Scholar 

  26. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, NY) 2007; 316: 1039–1043.

    Article  CAS  Google Scholar 

  27. Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010; 17: 77–88.

    Article  CAS  Google Scholar 

  28. Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 2008; 68: 9479–9487.

    Article  CAS  Google Scholar 

  29. Kentsis A, Reed C, Rice KL, Sanda T, Rodig SJ, Tholouli E et al. Autocrine activation of the MET receptor tyrosine kinasein acute myeloid leukemia. Nat Med 2012; 18: 1118–1122.

    Article  CAS  Google Scholar 

  30. Singleton KR, Kim J, Hinz TK, Marek LA, Casas-Selves M, Hatheway C et al. A receptor tyrosine kinasenetwork composed of fibroblast growth factor receptors, epidermal growth factor receptor, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, and hepatocyte growth factorreceptor drives growth and survival of head and neck squamous carcinoma cell lines. Mol Pharmacol 2013; 83: 882–893.

    Article  CAS  Google Scholar 

  31. Morse DL, Gillies RJ . Molecular imaging and targeted therapies. Biochem Pharmacol 2010; 80: 731–738.

    Article  CAS  Google Scholar 

  32. Astsaturov I, Ratushny V, Sukhanova A, Einarson MB, Bagnyukova T, Zhou Y, et al. Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci Signal 2010; 3: ra67.

    Article  Google Scholar 

  33. Ju L, Zhou C . Association of integrin beta1 and c-MET in mediating EGFR TKI gefitinib resistance in non-small cell lung cancer. Cancer Cell Int 2013; 13: 15.

    Article  CAS  Google Scholar 

  34. Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF, Wang YC et al. beta1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res 2011; 13: R84.

    Article  CAS  Google Scholar 

  35. Lesniak D, Xu Y, Deschenes J, Lai R, Thoms J, Murray D et al. Beta1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer. Cancer Res 2009; 69: 8620–8628.

    Article  CAS  Google Scholar 

  36. Oh YM, Song YJ, Lee SB, Jeong Y, Kim B, Kim GW et al. A new anti-c-Met antibody selected by a mechanism-based dual-screening method: therapeutic potential in cancer. Mol Cells 2012; 34: 523–529.

    Article  CAS  Google Scholar 

  37. Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ et al. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 2012; 287: 28087–28098.

    Article  CAS  Google Scholar 

  38. Zhang Y, Guessous F, Kofman A, Schiff D, Abounader R . XL-184 a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC. IDrugs 2010; 13: 112–121.

    PubMed  PubMed Central  Google Scholar 

  39. Zhu L, Somlo G, Zhou B, Shao J, Bedell V, Slovak ML, et al. Fibroblast growth factorreceptor 3 inhibition by short hairpin RNAs leads to apoptosis in multiple myeloma. Mol Cancer Ther 2005; 4: 787–798.

    Article  CAS  Google Scholar 

  40. Mohammadi M, Froum S, Hamby JM, Schroeder MC, Panek RL, Lu GH, et al. Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain. EMBO J 1998; 17: 5896–5904.

    Article  CAS  Google Scholar 

  41. Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptorfamily of receptor tyrosine kinase. J Med Chem 2011; 54: 7066–7083.

    Article  CAS  Google Scholar 

  42. Vogler M, Furdas SD, Jung M, Kuwana T, Dyer MJ, Cohen GM . Diminished sensitivity of chronic lymphocytic leukemia cells to ABT-737 and ABT-263 due to albumin binding in blood. Clin Cancer Res 2010; 16: 4217–4225.

    Article  CAS  Google Scholar 

  43. Janne PA, Gray N, Settleman J . Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov 2009; 8: 709–723.

    Article  CAS  Google Scholar 

  44. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010; 9: 1956–1967.

    Article  CAS  Google Scholar 

  45. Iida M, Brand TM, Campbell DA, Starr MM, Luthar N, Traynor AM et al. Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab. Cancer Biol Ther 2013; 14: 481–491.

    Article  CAS  Google Scholar 

  46. Langsenlehner U, Renner W, Yazdani-Biuki B, Eder T, Wascher TC, Paulweber B et al. Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk. Breast Cancer Res Treat 2006; 97: 67–72.

    Article  CAS  Google Scholar 

  47. Tuck AB, Elliott BE, Hota C, Tremblay E, Chambers AF . Osteopontin-induced, integrin-dependent migration of human mammary epithelial cells involves activation of the hepatocyte growth factorreceptor (Met). J Cell Biochem 2000; 78: 465–475.

    Article  CAS  Google Scholar 

  48. Burke PA, DeNardo SJ, Miers LA, Lamborn KR, Matzku S, DeNardo GL . Cilengitide targeting of alpha(v)beta(3) integrin receptor synergizes with radioimmunotherapy to increase efficacy and apoptosis in breast cancer xenografts. Cancer Res 2002; 62: 4263–4272.

    CAS  PubMed  Google Scholar 

  49. Zhang YW, Staal B, Essenburg C, Su Y, Kang L, West R et al. MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptorinhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth. Cancer Res 2010; 70: 6880–6890.

    Article  CAS  Google Scholar 

  50. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM et al. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 2013; 23: 121–128.

    Article  CAS  Google Scholar 

  51. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483: 100–103.

    Article  CAS  Google Scholar 

  52. Harbinski F, Craig VJ, Sanghavi S, Jeffery D, Liu L, Sheppard KA et al. Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discov 2012; 2: 948–959.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

LMW, SW and JCM are supported in part by NCI Grants CA51008 and CA50633. We thank Sandra A Jablonski, Wei Xu and Kyutaeg Lee for technical assistance. We are grateful for the support of the Lombardi Comprehensive Cancer Center’s Genomics and Epigenomics Shared Resource.

Author information

Author notes

  1. B Kim and S Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea

    B Kim, J M Lee, Y Jeong, T Ahn, D-S Son, H W Park, H-s Yoo, Y-J Song, E Lee, Y M Oh, S B Lee, J Choi, P H Song & K-A Kim

  2. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA

    S Wang, J C Murray & L M Weiner

  3. Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA

    Y Zhou

Authors
  1. B Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J M Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D-S Son
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H W Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H-s Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y-J Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. E Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Y M Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S B Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. J Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. J C Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Y Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P H Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. K-A Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. L M Weiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to K-A Kim or L M Weiner.

Ethics declarations

Competing interests

The following authors are employed by the Samsung Advanced Institute of Technology: BK, JML, YJ, TA, D-SS, HWP, H-sY, Y-JS, EL, YMO, SBL, JC, PHS and K-AK.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, B., Wang, S., Lee, J. et al. Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy. Oncogene 34, 1083–1093 (2015). https://doi.org/10.1038/onc.2014.51

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.51

This article is cited by

Search

Advanced search

Quick links