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Poster display

1728 - Biomarker driven combinations for synthetic lethal approaches in KRAS mutant (KRASm) lung adenocarcinoma (LAC)

Date

10 Oct 2016

Session

Poster display

Presenters

Chiara Lazzari

Citation

Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392

Authors

C. Lazzari1, A. Verlicchi2, C. Codony Servat3, J. Codony Servat3, M.A. Molina Vila3, I. Chaib4, J.L. Ramírez Serrano5, N. Karachaliou6, F. de Marinis1, R. Rosell5

Author affiliations

  • 1 Divisione Di Oncologica Toracica, Istituto Europeo di Oncologia, 20141 - Milano/IT
  • 2 Dipartimento Di Oncologia/ematologia, Ospedale Civile di Ravenna - S.ta Maria delle Croci, 48121 - Ravenna/IT
  • 3 Laboratory Of Cellular And Molecular Biology, Pangaea Biotech SL, IOR Quirón-Dexeus University Institute, 08028 - Barcelona/ES
  • 4 Laboratory Of Cellular And Molecular Biology, Institut d'Investigació en Ciències Germans Trias i Pujol, 08916 - Badalona/ES
  • 5 Translational Research Unit, Laboratory Of Molecular Biology, Catalan Institute of Oncology (ICO Badalona), Hospital Germans Trias i Pujol, 08916 - Badalona/ES
  • 6 Medical Oncology Service, Instituto Oncológico Dr Rosell (IOR), Hospital Universitario Quirón-Dexeus, 08028 - Barcelona/ES
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Resources

Abstract 1728

Background

MEK inhibition is interesting but still has modest efficacy in KRASm LAC patients. STAT3 activation and AXL mediated epithelial-to-mesenchymal transition cause resistance to MEK inhibition. p21-activated kinase 1 (PAK1) regulates ERK activation and its role in KRASm LAC warrants further investigation. YAP1 suppression increases trametinib efficacy in KRASm LAC cells. We have explored the role of STAT3, AXL, PAK1 and YAP1 in KRASm LAC cells and developed a rationale for combinatorial strategies.

Methods

Quantitative real-time PCR gene expression analysis was performed in 4 KRASm LAC cell lines (H23, A549, H460 and Calu6). The MEK inhibitor (i) selumetinib was combined with evodiamine (STAT3i), R428 (AXLi) or ivermectin (dual YAP1-PAK1i). Cell viability was assessed by the thiazolyl blue assay and the combination index (CI) was calculated for the analysis of drug interactions.

Results

We first evaluated the effect of selumetinib in the 4 KRASm LAC cell lines. H23 and H460 were less sensitive to selumetinib than A549 and Calu6. Among the cell lines examined, H23 cells had the highest STAT3 mRNA expression and the combination of selumetinib with evodiamine synergistically suppressed cell viability (CI = 0.8). The combination of R428 with selumetinib was also synergistic in H23 cells (CI = 0.58) that have moderate AXL mRNA expression. High PAK1 mRNA expression was detected in the A549 selumetinib-sensitive cell line, and the addition of the dual PAK1-YAP1i, ivermectin, to selumetinib increased the effect of MEK inhibition alone (CI = 0.17). To our surprise, the combination of ivermectin with selumetinib was not synergistic in the H23 cells that overexpress YAP1. H460 and Calu-6 cells have moderate or low STAT3, AXL, PAK1 and YAP1 expression. Further cell viability experiments as well as immunoblotting and biomarkers analysis in clinical tumor samples are ongoing.

Conclusions

The heterogeneous biology of KRASm LAC may partially explain the difficulties encountered in the development of efficient therapies. Our data, until now, identify STAT3, AXL and PAK1 as potential biomarkers and the targeting of them as a potential synergistic strategy to combine with MEK inhibition.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

This work was supported by grants from the La Caixa Foundation and Red Tematica de Investigacion Cooperativa en Cancer (RTICC; grant RD12/0036/ 0072).

Disclosure

All authors have declared no conflicts of interest.

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