Author of

• 12418

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  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

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

  • 12440

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    P3.05-023 - Treatment with the mTOR kinase inhibitor CC-223 overcomes resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in non-small cell lung cancer cells (ID 3429)

    09:30 - 09:30  |  Author(s): E. Filvaroff
    • Abstract

    Background
    Activation of the mTOR pathway is a common down-stream mechanism of resistance to Epidermal Growth Factor receptor (EGFR) tyrosine kinase inhibitors. CC-223 (Celgene) is an mTOR kinase inhibitor under clinical development. We evaluated CC-223 in combination with erlotinib to overcome resistance to EGFR tyrosine kinase inhibition in non-small cell lung cancer (NSCLC) cell lines and xenografts in nude mice.

    Methods
    A panel of 18 NSCLC cell lines was used to evaluate the effect of erlotinib and CC-223 treatment on cell growth using an MTT assay. Intermediately (IC50 >1 and <10 mM) and highly (IC50 >10 mM) resistant cell lines to erlotinib were used in analyses of additive/synergistic effects for the combination treatment with CC-223.

    Results
    CC-223 demonstrated anti-proliferative activity in NSCLC cell lines with various degrees of sensitivity as reflected in different IC50 values, ranging from 0.15 to 12 mM. In combination with erlotinib, CC-223 showed synergistic anti-proliferative effects in NSCLC cells resistant to erlotinib with combination indices as low as 0.1-0.2. In vivo studies in mice xenografts demonstrated a strong synergistic effect of the combination treatment of erlotinib and CC-223 with a 90% decrease of tumor volume compared to untreated and 88% compared to erlotinib treated for A549 cells. IHC analyses of apoptosis and proliferation in the tumors are ongoing; mature data will be presented at the meeting.

    Conclusion
    The mTOR kinase inhibitor CC-223 demonstrated anti-proliferative activity in a panel of NSCLC cell lines. In NSCLC cells resistant to the EGFR tyrosine kinase inhibitor erlotinib, combining erlotinib with CC-223 demonstrated a synergistic anti-proliferative effect. In vivo studies of tumors in xenografted mice also demonstrated synergistic anti-tumor effects with the combination treatment even in erlotinib resistant tumors. The present data suggest that mTOR inhibition using the mTOR kinase inhibitor CC-223 may be a therapeutic strategy to overcome resistance to EGFR tyrosine kinase inhibitors in NSCLC.