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Peng Cao



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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-14 - HLA-E and FAT1 in Head and Neck and Lung Cancer. The Effect of Osimertinib or Olmutinib with Artesunate (Dihydroartemisinin) (ID 912)

      09:45 - 18:00  |  Author(s): Peng Cao

      • Abstract
      • Slides

      Background

      Cisplatin and cetuximab have little effect in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LSCC). HLA-E expression suppressed the cetuximab effect and HLA-E is overexpressed in both HNSCC and LSCC. In addition, FAT1 inactivating mutations are present in 30% of HNSCCs and 19% of LSCCs. Dihydroartemisinin (DHA) inhibits STAT3 and increases cisplatin effect in HNSCC. Osimertinib and olmutinib increase intracellular accumulation of doxorubicin by blocking the efflux function of ABC transporters. We posit that osimertinib or olmutinib, plus DHA, could have activity in the HNSCC cell lines, FaDu and CAL27, with loss of FAT1 expression.

      Method

      Osimertinib and olmutinib plus DHA were tested in the FaDu and CAL27 cell lines. Tumor cell proliferation assays (MTTs) and mouse xenografts were performed, and western blotting analysis was carried out. FaDu CTXR clone #3 (cetuximab-resistant, a gift from Bhola) and SCCNC4 (EGFR exon 20 S768_D770 dup, a gift from Hermsen) were also examined.

      Result

      1. DHA decreased HLA-E protein levels in a dose dependent manner in the FaDu CTXR.

      2. DHA was able to induce the expression of FAT1 in FaDu and CAL27 cells.

      3. Osimertinib plus DHA had a synergistic effect (<1, Combination index (CI)=0.468 and 0.593 in FaDu and CAL27, respectively). Olmutinib with DHA was also synergistic (CI=0.773 and 0.762 in FaDu and CAL27).

      4. Osimertinib plus DHA was validated in vivo in FaDu and CAL27 mice xenografts with significant tumor regression.

      5. Osimertinib plus DHA suppress the expression of onco-effectors: STAT3, Src, YAP and AXL.

      6. Osimertinib plus DHA was also synergistic in SCCNC4 (CI=0.596).

      Conclusion

      The findings indicate that DHA can revert resistance to cetuximab by repressing the expression of HLA-E. The combination of DHA plus osimertinib was active in the parental FaDu, but not in FaDu CTXR. For tumors with lack of FAT1 expression, the use of DHA reactivates FAT1 and YAP1 inhibition was noted. DHA has been tested for the treatment of systemic lupus erythematosus (SLE), orally, daily for 2 years. The results encourage development of clinical trials with DHA to re-sensitize HNSCC and LSCC cells to cetuximab-based therapy.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-45 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant Adenocarcinoma and Squamous Cell Carcinoma (ID 789)

      10:15 - 18:15  |  Author(s): Peng Cao

      • Abstract

      Background

      p21-activated kinase 1 (PAK1) stimulates growth and metastasis in several types of tumors, including non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCi) is an enzyme highly expressed in NSCLC that regulates PAK1 signaling. To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR/KRAS mutant adenocarcinoma or squamous cell carcinoma (SCC) cell lines by combination therapy using PAK1 inhibitor and PKCι inhibitor.

      Method

      Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carries EGFR and KRAS mutations, respectively, and H520 (PAK1 amplified squamous cell carcinoma). Cell viability assays and western blotting were applied to evaluate the effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor). Since IPA-3 is only for laboratory use, we explored alternative PAK-1 inhibitor and tested combination effect with auranofin.

      Result

      IPA-3 plus auranofin was highly synergistic (Combination index was less than 0.4) in EGFR mutant adenocarcinoma (HCC827), KRAS mutant adenocarcinoma (H23) and SCC with PAK1 amplification (H520) cell lines in MTT assay and colony forming assay. We revealed OTSSP167 (a MELK inhibitor in phase I/II trials) inhibits phosphorylated PAK1 and combination of OTSSP167 plus auranofin showed similar synergism in the 3 cell lines. 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.

      Conclusion

      The combination of IPA-3 plus auranofin is promising treatment in different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification. OTSSP167 also works as PAK1 inhibitor. The therapeutic effect of PAK-1 inhibitor and PKCι inhibitor was validated using OTSSP167 plus auranofin.