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Medical Oncology

, 34:175 | Cite as

EGFR and KRAS mutations do not enrich for the activation of IL-6, JAK1 or phosphorylated STAT3 in resected lung adenocarcinoma

  • Timothy D. Clay
  • Prudence A. Russell
  • Hongdo Do
  • Vijaya Sundararajan
  • Matthew Conron
  • Gavin M. Wright
  • Benjamin Solomon
  • Alexander Dobrovic
  • Sue-Anne McLachlan
  • Melissa M. Moore
Original Paper

Abstract

Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) against EGFR mutant lung adenocarcinoma develops after a median of nine to thirteen months. Upregulation of the interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway may be a potential source of resistance to EGFR TKIs. We undertook a detailed assessment of the IL-6/JAK1/phosphorylated STAT3 (pSTAT3) pathway in resected lung adenocarcinoma specimens, with special interest in whether the presence of an EGFR mutation enriched for pSTAT3 positivity. Tumours from 143 patients with resected lung adenocarcinoma were assessed. EGFR and KRAS mutation status were scanned for with high-resolution melting and confirmed by polymerase chain reaction. Immunohistochemisty (IHC) was performed for IL-6, gp130, JAK1 and pSTAT3. Two methods for assigning IHC positivity were assessed (the presence of any positivity, and the presence of positivity at an H score >40). We found statistically significant associations between IL-6, JAK1 and pSTAT3 measured by IHC, consistent with the activation of the pathway in clinical specimens. No relationship was demonstrated between members of this pathway and oncogenic mutations in EGFR or KRAS. However, a proportion of tumours with EGFR mutations showed staining for IL-6, JAK1 and pSTAT3. No correlations with clinicopathologic features or survival outcomes were found for IL-6, JAK1 or pSTAT3 staining. The presence of EGFR or KRAS mutations did not enrich for the activation of IL-6, JAK1 or pSTAT3. pSTAT3 may still play a role in resistance to EGFR TKIs in clinical practice.

Keywords

Lung adenocarcinoma EGFR mutation IL-6 JAK1 pSTAT3 

Notes

Acknowledgements

Funding for this study was provided by St. Vincent’s Hospital research endowment fund. Dr Clay was supported by Australian Postgraduate Award from the University of Melbourne.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12032_2017_1031_MOESM1_ESM.jpg (183 kb)
Supplementary Figure 1 (a–d) Examples of Immunohistochemistry Staining for gp130 (gp130 antibody: Santa Cruz Biotechnology, Dallas TX, USA). Even Cytoplasmic Staining was observed. a: no staining; b: 1+ staining; c: 2+ staining; d: 3+ staining (JPEG 182 kb)
12032_2017_1031_MOESM2_ESM.docx (18 kb)
Supplementary material 2 (DOCX 17 kb)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Timothy D. Clay
    • 1
    • 2
  • Prudence A. Russell
    • 3
    • 4
  • Hongdo Do
    • 4
    • 5
    • 6
  • Vijaya Sundararajan
    • 2
  • Matthew Conron
    • 2
    • 7
  • Gavin M. Wright
    • 8
    • 9
    • 10
  • Benjamin Solomon
    • 11
    • 12
  • Alexander Dobrovic
    • 4
    • 5
    • 6
  • Sue-Anne McLachlan
    • 2
    • 13
  • Melissa M. Moore
    • 2
    • 13
  1. 1.St John of God HospitalSubiacoAustralia
  2. 2.Department of Medicine, St Vincent’s Hospital, Melbourne Medical SchoolUniversity of MelbourneMelbourneAustralia
  3. 3.Department of PathologySt Vincent’s Hospital, MelbourneMelbourneAustralia
  4. 4.Department of PathologyUniversity of MelbourneMelbourneAustralia
  5. 5.Translational Genomics and Epigenomics LaboratoryOlivia Newton-John Cancer Research InstituteMelbourneAustralia
  6. 6.School of Cancer MedicineLa Trobe UniversityMelbourneAustralia
  7. 7.Department of Respiratory MedicineSt Vincent’s Hospital, MelbourneMelbourneAustralia
  8. 8.Department of Thoracic SurgerySt Vincent’s Hospital, MelbourneMelbourneAustralia
  9. 9.Department of Thoracic SurgeryPeter MacCallum Cancer CentreMelbourneAustralia
  10. 10.Department of SurgeryUniversity of MelbourneMelbourneAustralia
  11. 11.Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneAustralia
  12. 12.Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia
  13. 13.Department of Medical OncologySt Vincent’s Hospital, MelbourneMelbourneAustralia

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