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V. Gregorc



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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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      58P - Co-treatment of trametinib (MEK inhibitor) with TPX-0005 (Src/FAK/JAK2 inhibitor) synergistic in KRAS mutant NSCLC cell lines and CDCP1 acts as a biomarker in KRAS mutant patients (p) (ID 407)

      12:30 - 13:00  |  Author(s): V. Gregorc

      • Abstract
      • Slides

      Background:
      KRAS mutant lung adenocarcinoma has a dismal prognosis. In the current study, we identified combination targets for trametinib, a MEK inhibitor, which acts downstream of KRAS to suppress signaling through MAPK cascade. However, we have previously shown that selumetinib (MEK inhibitor) in KRAS mutant NSCLC cells caused a rebound of ERK, AKT and STAT3, as well as YAP phosphorylation (Y357), NOTCH3 and activation of RTKs, AXL and MET. We hypothesize that, in KRAS mutant NSCLC, suppression of MAPK could lead to activation of Src-YAP1-AXL-MET. Since CUB domain-containing protein 1 (CDCP1) activates Src, we consider that CDCP1 could be a biomarker of Src activation.

      Methods:
      Cell viability assay, colony formation assay and western blotting were performed to assess the treatment of trametinib plus TPX-0005 in a panel of 8 NSCLC cell lines: A549, Calu6, H23, H460, H2009, H2030, H441, H727. Synergy between trametinib and TPX-0005 was assessed via the Chou-Talalay method to estimate the combination index (CI). CI values <0.7 were considered synergistic, with decreasing CI values indicating greater synergy. We examined tumor samples of 32 KRAS mutant NSCLC p for CDCP1 mRNA levels.

      Results:
      The combination of trametinib with TPX-0005 was synergistic or additive in all cell lines tested. H23 and Calu6 were the most synergistic, followed by H441 and H2030. In the majority of cell lines examined, the colony formation assay resulted in an almost complete abrogation of tumor cell colonies, particularly in the H23 and A549. Western blotting indicated that the combination of trametinib with TPX-0005 abolished the phosphorylation of STAT3 (Y705), paxillin (Y118), a readout of FAK, and Src (Y416). The median PFS of 32 KRAS mutant NSCLC p was 2.5 months and the overall survival was 13.4 months. According to CDCP1 levels, the median PFS was 3.5 months for those with low CDCP1 and 1.4 months for those with high CDCP1 (P = 0.012). The median survival was 16.3 months for p with low CDCP1, and only 3.2 months for those with high CDCP1 (P = 0.023).

      Conclusions:
      The combination of trametinib plus TPX-0005 shows significant in-vitro activity in the majority of KRAS mutant NSCLC cell lines and the mRNA levels of CDCP1 could be a biomarker in KRAS mutant NSCLC p, indicating the activation of Src-YAP signaling. Clinical trials with the combination of MEK inhibitors with TPX-0005 are warranted.

      Clinical trial identification:


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

      Funding:
      Fundació Obra Social “La Caixa”

      Disclosure:
      All authors have declared no conflicts of interest.

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