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Carles Codony-Servat



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    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.03-14 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant and Squamous Cell Non-Small Cell Lung Cancer (NSCLC) (ID 12342)

      16:45 - 18:00  |  Author(s): Carles Codony-Servat

      • Abstract
      • Slides

      Background

      To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR, KRAS and Squamous cell carcinoma (SCC) cell lines.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      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 auranofin (PKCi inhibitor) plus IPA-3 (PAK1 inhibitor). Since IPA-3 is only for laboratory use, we also tested auranofin in combination with OTSSP167 (a MELK inhibitor in phase I trials), which, in our experience, inhibits pPAK1 (Thr423 and Thr212 in the HCC827 cell line).

      4c3880bb027f159e801041b1021e88e8 Result

      Auranofin plus IPA-3 was highly synergistic (CI less than 0.4) in EGFR mutant (HCC827), KRAS mutant (H23) and SCC with PAK1 amplification (H520 cells). Similar synergism was found with the combination of auranofin plus OTSSP167 in the 3 cell lines (Figure). the combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET and CDCP1. We created EGFR mutant gefitinib and osimertinib resistant cell lines (PC9-GR3, GR4, OR2, OR4). Auranofin plus IPA-3 was highly synergistic in all cell lines.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These observations suggest that the combination of auranofin with OTSSP167 can be used for treatment of different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification.

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