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

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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.

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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.

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Authors and Affiliations

  1. St John of God Hospital, Suite C202, 12 Salvado Road, Subiaco, 6008, Australia

    Timothy D. Clay

  2. Department of Medicine, St Vincent’s Hospital, Melbourne Medical School, University of Melbourne, Melbourne, Australia

    Timothy D. Clay, Vijaya Sundararajan, Matthew Conron, Sue-Anne McLachlan & Melissa M. Moore

  3. Department of Pathology, St Vincent’s Hospital, Melbourne, Melbourne, Australia

    Prudence A. Russell

  4. Department of Pathology, University of Melbourne, Melbourne, Australia

    Prudence A. Russell, Hongdo Do & Alexander Dobrovic

  5. Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia

    Hongdo Do & Alexander Dobrovic

  6. School of Cancer Medicine, La Trobe University, Melbourne, Australia

    Hongdo Do & Alexander Dobrovic

  7. Department of Respiratory Medicine, St Vincent’s Hospital, Melbourne, Melbourne, Australia

    Matthew Conron

  8. Department of Thoracic Surgery, St Vincent’s Hospital, Melbourne, Melbourne, Australia

    Gavin M. Wright

  9. Department of Thoracic Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia

    Gavin M. Wright

  10. Department of Surgery, University of Melbourne, Melbourne, Australia

    Gavin M. Wright

  11. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia

    Benjamin Solomon

  12. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia

    Benjamin Solomon

  13. Department of Medical Oncology, St Vincent’s Hospital, Melbourne, Melbourne, Australia

    Sue-Anne McLachlan & Melissa M. Moore

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  1. Timothy D. Clay
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Correspondence to Timothy D. Clay.

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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.

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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)

Supplementary material 2 (DOCX 17 kb)

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Clay, T.D., Russell, P.A., Do, H. et al. EGFR and KRAS mutations do not enrich for the activation of IL-6, JAK1 or phosphorylated STAT3 in resected lung adenocarcinoma. Med Oncol 34, 175 (2017). https://doi.org/10.1007/s12032-017-1031-1

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