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M. Okada

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    Poster Display session (Friday) (ID 65)

    • Event: ELCC 2018
    • Type: Poster Display session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 4/13/2018, 12:30 - 13:00, Hall 1
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      25P - A non-pathway-specific approach in EGFR and KRAS mutant or squamous cell histology non-small cell lung cancer (NSCLC) (ID 551)

      12:30 - 13:00  |  Author(s): M. Okada

      • Abstract

      p21-activated kinase 1 (PAK1) stimulates growth and metastasis in several types of tumors, including NSCLC. Protein kinase C iota (PKCi) is an enzyme highly expressed in NSCLC that regulates PAK1 signaling. We have previously shown that cancer pathway-specific intervention, like EGFR inhibitors in EGFR mutant NSCLC, results in parallel compensatory activation of other pathways, including the receptor tyrosine kinases AXL and MET, the transmembrane protein CUB domain-containing protein-1 (CDCP1) or the transcriptional regulators STAT3 and YAP1. We have now explored whether a non-pathway-specific approach can be efficient in three subsets of NSCLC.

      Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carry EGFR and KRAS mutations respectively, and H520 PAK1 amplified squamous NSCLC cells. Cell viability assays and western blotting were applied to evaluate the effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCi inhibitor). We used a Chou-Talalay modified method for drug combination studies that offers quantitative definition for additive effect (combination index [CI] = 1), synergism (CI < 1), and antagonism (CI > 1).

      We found a differential PAK1 expression or activation profile in the three models, with H520 cells being the ones with the highest PAK1 expression and activation. IPA-3 plus auranofin was highly synergistic in HCC827, H23 and H520 cells with CIs of less than 0.4. In the EGFR mutant HCC827 cell line, IPA-3 plus afatinib or osimertinib was additive (CI = 0.9), or slightly synergistic (CI = 0.8). In the same cell line, the combination of IPA-3 plus auranofin abrogated EGFR and downstream signaling (ERK, AKT, STAT3, YAP1) and inhibited the expression and activation of AXL, MET and CDCP1. IPA-3 plus auranofin was, similarly, highly synergistic in H23 (CI = 0.3) and H520 (CI = 0.3) cells.

      For the first time, we are reporting that a non-pathway specific combination can be effective in EGFR and KRAS mutant as well as squamous NSCLC. The combination could control the counter-regulatory pathways that are made apparent and ultimately cause resistance when a pathway specific-intervention is applied.

      Clinical trial identification:

      Legal entity responsible for the study:
      IGTP, Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain

      International Association for the Study of Lung Cancer (IASLC)

      All authors have declared no conflicts of interest.