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  P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11545

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    P2.06-002 - Protein tyrosine kinase substrates profiling to detect short-term survivors in early stage lung adenocarcinoma (ID 165)

    09:30 - 09:30  |  Author(s): S. Hillinger
    • Abstract

    Background
    With existing therapeutic efforts, patients with lung cancer have a poor prognosis. Assessment of tumor size, lymph node status and presence of metastases is currently applied for determining prognosis and treatment modality, but predicted and real outcomes can vary significantly. Biomarkers with reliable prognostic significance are therefore of utmost importance but due to a lack of immediate correlation between levels of protein and their corresponding mRNA, a screen based on the kinase activity become a promising option to circumvent this limitation with the tremendeous advantage of focusing on therapeutically targetable enzymatic activities. Several protein tyrosine kinase inhibitors already clinically approved for the treatment of lung cancer are targeting some of the 400 types of DNA signatures described in silico in the human genome. The aim of this study is to clarify the following hypothesis: Is the in vitro multiplexed tyrosine phosphorylation of substrates a possible approach to molecularly classify the kinome of early stage lung adenocarcinoma biopsies and obtain a diagnostic /prognostic signature correlating with the survival of patients?

    Methods
    We have built a tumor bank of frozen malignant and non-neoplastic lung surgically obtained specimen and recorded all clinical interventions, follow up treatments and outcome for each of our patients. We incubated TNM stage 1 and 2 lung adenocarcinoma kinomes on PamChip®4 microarrays and followed the kinetics of the multiplexed tyrosine phosphorylation for 144 peptides substrates. Image quantification, quality control, statistical analysis and interpretation of data were performed with the BionavigatoR software.

    Results
    We screened 84 paired malignant TNM stage 1 and 2 lung adenocarcinoma and non-neoplastic lung biopsies for the multiplex tyrosine phosphorylation of substrates immobilized on a PamChip®4microarrays. Based on a 76-point ‘response-signature’ we obtained 73 % of correct prediction with a 10 fold cross validation PLS-DA analysis in TNM stage 1 lung adenocarcinoma biopsies. Moreover, we detected 26 peptides substrates significantly more inhibited in kinomes of long-term survivors than in kinomes of the short-term survivors.

    Conclusion
    In frozen biopsies of TNM stage I adenocarcinoma and with a PLS-DA analysis applied to a 76-point ‘response-signature’ we present the feasibility to discriminate between long-term and short-term survivors. Furthermore, the found differences in enzymatic activities in lung biopsies may result in the identification of new targets in future anti lung cancer therapy efforts.