Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
November-2017 Volume 51 Issue 5

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
November-2017 Volume 51 Issue 5

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer

  • Authors:
    • Ryohei Yoshida
    • Takaaki Sasaki
    • Yoshinori Minami
    • Yukiko Hibino
    • Shunsuke Okumura
    • Masatoshi Sado
    • Naoyuki Miyokawa
    • Satoshi Hayashi
    • Masahiro Kitada
    • Yoshinobu Ohsaki
  • View Affiliations / Copyright

    Affiliations: Respiratory Center, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan, Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan
  • Pages: 1533-1540
    |
    Published online on: September 28, 2017
       https://doi.org/10.3892/ijo.2017.4140
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Lee YJ, Kim JH, Kim SK, Ha SJ, Mok TS, Mitsudomi T and Cho BC: Lung cancer in never smokers: Change of a mindset in the molecular era. Lung Cancer. 72:9–15. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Oxnard GR, Binder A and Jänne PA: New targetable oncogenes in non-small-cell lung cancer. J Clin Oncol. 31:1097–1104. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D and Thomas R: EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 14:4275–4283. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, et al: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 363:1693–1703. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, et al: CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): A single-arm, open-label, phase 1–2 study. Lancet Oncol. 14:590–598. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Shaw AT and Engelman JA: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 370:2537–2539. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Katayama R, Shaw AT, Khan TM, Mino-Kenudson M, Solomon BJ, Halmos B, Jessop NA, Wain JC, Yeo AT, Benes C, et al: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 4:120ra172012. View Article : Google Scholar : PubMed/NCBI

9 

Yamaguchi N, Lucena-Araujo AR, Nakayama S, de Figueiredo-Pontes LL, Gonzalez DA, Yasuda H, Kobayashi S, Costa DB and Dual ALK: Dual ALK and EGFR inhibition targets a mechanism of acquired resistance to the tyrosine kinase inhibitor crizotinib in ALK rearranged lung cancer. Lung Cancer. 83:37–43. 2014. View Article : Google Scholar :

10 

Niederst MJ and Engelman JA: Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal. 6:re62013. View Article : Google Scholar : PubMed/NCBI

11 

Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Frias RL, Gainor JF, Amzallag A, Greninger P, et al: Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. 346:1480–1486. 2014. View Article : Google Scholar : PubMed/NCBI

12 

An R, Wang Y, Voeller D, Gower A, Kim IK, Zhang YW and Giaccone G: CRKL mediates EML4-ALK signaling and is a potential therapeutic target for ALK-rearranged lung adenocarcinoma. Oncotarget. 7:29199–29210. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Sang J, Acquaviva J, Friedland JC, Smith DL, Sequeira M, Zhang C, Jiang Q, Xue L, Lovly CM, Jimenez JP, et al: Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov. 3:430–443. 2013. View Article : Google Scholar : PubMed/NCBI

14 

Katayama R, Khan TM, Benes C, Lifshits E, Ebi H, Rivera VM, Shakespeare WC, Iafrate AJ, Engelman JA and Shaw AT: Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Natl Acad Sci USA. 108:7535–7540. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Sequist LV, Gettinger S, Senzer NN, Martins RG, Jänne PA, Lilenbaum R, Gray JE, Iafrate AJ, Katayama R, Hafeez N, et al: Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol. 28:4953–4960. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Tonack S, Jenkinson C, Cox T, Elliott V, Jenkins RE, Kitteringham NR, Greenhalf W, Shaw V, Michalski CW, Friess H, et al: iTRAQ reveals candidate pancreatic cancer serum biomarkers: Influence of obstructive jaundice on their performance. Br J Cancer. 108:1846–1853. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Chen Z, Sasaki T, Tan X, Carretero J, Shimamura T, Li D, Xu C, Wang Y, Adelmant GO, Capelletti M, et al: Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. Cancer Res. 70:9827–9836. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S, Khainovski N, Pillai S, Dey S, Daniels S, et al: Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics. 3:1154–1169. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, et al: Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 17:461–469. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Kang CW, Jang KW, Sohn J, Kim SM, Pyo KH, Kim H, Yun MR, Kang HN, Kim HR, Lim SM, et al: Antitumor activity and acquired resistance mechanism of dovitinib (TKI258) in RET-rearranged lung adenocarcinoma. Mol Cancer Ther. 14:2238–2248. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Subbannayya Y, Syed N, Barbhuiya MA, Raja R, Marimuthu A, Sahasrabuddhe N, Pinto SM, Manda SS, Renuse S, Manju HC, et al: Calcium calmodulin dependent kinase kinase 2 - a novel therapeutic target for gastric adenocarcinoma. Cancer Biol Ther. 16:336–345. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Xu J, Li L, Yu G, Ying W, Gao Q, Zhang W, Li X, Ding C, Jiang Y, Wei D, et al: The neddylation-cullin 2-RBX1 E3 ligase axis targets tumor suppressor RhoB for degradation in liver cancer. Mol Cell Proteomics. 14:499–509. 2015. View Article : Google Scholar :

23 

Schlaepfer DD and Hunter T: Evidence for in vivo phosphorylation of the Grb2 SH2-domain binding site on focal adhesion kinase by Src-family protein-tyrosine kinases. Mol Cell Biol. 16:5623–5633. 1996. View Article : Google Scholar : PubMed/NCBI

24 

Schlaepfer DD and Mitra SK: Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev. 14:92–101. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Bromann PA, Korkaya H and Courtneidge SA: The interplay between Src family kinases and receptor tyrosine kinases. Oncogene. 23:7957–7968. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Parsons JT and Parsons SJ: Src family protein tyrosine kinases: Cooperating with growth factor and adhesion signaling pathways. Curr Opin Cell Biol. 9:187–192. 1997. View Article : Google Scholar : PubMed/NCBI

27 

Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH and Parsons SJ: c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J Biol Chem. 274:8335–8343. 1999. View Article : Google Scholar : PubMed/NCBI

28 

Belsches-Jablonski AP, Biscardi JS, Peavy DR, Tice DA, Romney DA and Parsons SJ: Src family kinases and HER2 interactions in human breast cancer cell growth and survival. Oncogene. 20:1465–1475. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Isozaki H, Ichihara E, Takigawa N, Ohashi K, Ochi N, Yasugi M, Ninomiya T, Yamane H, Hotta K, Sakai K, et al: Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases. Cancer Res. 76:1506–1516. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Tani T, Yasuda H, Hamamoto J, Kuroda A, Arai D, Ishioka K, Ohgino K, Miyawaki M, Kawada I, Naoki K, et al: Activation of EGFR bypass signaling by TGFα overexpression induces acquired resistance to alectinib in ALK-translocated lung cancer cells. Mol Cancer Ther. 15:162–171. 2016. View Article : Google Scholar

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Yoshida R, Sasaki T, Minami Y, Hibino Y, Okumura S, Sado M, Miyokawa N, Hayashi S, Kitada M, Ohsaki Y, Ohsaki Y, et al: Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer. Int J Oncol 51: 1533-1540, 2017.
APA
Yoshida, R., Sasaki, T., Minami, Y., Hibino, Y., Okumura, S., Sado, M. ... Ohsaki, Y. (2017). Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer. International Journal of Oncology, 51, 1533-1540. https://doi.org/10.3892/ijo.2017.4140
MLA
Yoshida, R., Sasaki, T., Minami, Y., Hibino, Y., Okumura, S., Sado, M., Miyokawa, N., Hayashi, S., Kitada, M., Ohsaki, Y."Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer". International Journal of Oncology 51.5 (2017): 1533-1540.
Chicago
Yoshida, R., Sasaki, T., Minami, Y., Hibino, Y., Okumura, S., Sado, M., Miyokawa, N., Hayashi, S., Kitada, M., Ohsaki, Y."Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer". International Journal of Oncology 51, no. 5 (2017): 1533-1540. https://doi.org/10.3892/ijo.2017.4140
Copy and paste a formatted citation
x
Spandidos Publications style
Yoshida R, Sasaki T, Minami Y, Hibino Y, Okumura S, Sado M, Miyokawa N, Hayashi S, Kitada M, Ohsaki Y, Ohsaki Y, et al: Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer. Int J Oncol 51: 1533-1540, 2017.
APA
Yoshida, R., Sasaki, T., Minami, Y., Hibino, Y., Okumura, S., Sado, M. ... Ohsaki, Y. (2017). Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer. International Journal of Oncology, 51, 1533-1540. https://doi.org/10.3892/ijo.2017.4140
MLA
Yoshida, R., Sasaki, T., Minami, Y., Hibino, Y., Okumura, S., Sado, M., Miyokawa, N., Hayashi, S., Kitada, M., Ohsaki, Y."Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer". International Journal of Oncology 51.5 (2017): 1533-1540.
Chicago
Yoshida, R., Sasaki, T., Minami, Y., Hibino, Y., Okumura, S., Sado, M., Miyokawa, N., Hayashi, S., Kitada, M., Ohsaki, Y."Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer". International Journal of Oncology 51, no. 5 (2017): 1533-1540. https://doi.org/10.3892/ijo.2017.4140
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team