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

  • 12433

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    P3.05-016 - Effective combination therapies with MEK inhibitors for the treatment of mutant-BRAF lung cancers. (ID 2657)

    09:30 - 09:30  |  Author(s): A. Rao
    • Abstract

    Background
    Targeted therapeutics to mutant-BRAF and MEK have demonstrated remarkable efficacy in BRAF[V600E] metastatic melanomas. Unexpectedly, similar responses to the BRAF inhibitor vemurafenib (PLX4032) were not observed in BRAF[V600E] colorectal cancers (CRCs). Approximately 3% of lung cancers carry BRAF mutations, with only half being BRAF[V600E]. Recent case studies have reported responses to vemurafenib in patients with BRAF[V600E] NSCLC, suggesting that inhibition of the MAPK pathway with targeted therapeutics may be a feasible treatment strategy for BRAF-mutant lung cancers.

    Methods
    A panel of NSCLC cell lines carrying BRAF[V600E], BRAF[G469A], BRAF[G466V] and BRAF[L597V] mutations were assessed for responses to the MEK inhibitors Selumetinib (AZD6244), Trametinib (GSK1120212) and PD-325901 using standard drug response assays. Cell lines were also analysed by Western Blot analysis at various time-points following treatment with MEK inhibitors to determine the effects on the signalling pathways within the cells.

    Results
    Although all the cell lines displayed some sensitivity to MEK inhibition, the level of cell death observed with MEK inhibitors as single agents was minimal. The responses to MEK inhibition varied in cell lines carrying the same BRAF mutation indicating that other genetic differences could influence responses to inhibition of the MAPK pathway. Inherent co-expression of specific Receptor Tyrosine Kinases such as EGFR was detected in some of the cell lines and an increase in P-EGFR was observed following MEK inhibition. Increase in P-EGFR has been reported as the mechanism of resistance to vemurafenib in BRAF-mutant CRCs. In cell lines carrying non-V600E BRAF mutations, MEK inhibitor treatment also resulted in an increase in P-MEK, revealing a release of the MAPK pathway negative feedback resulting in upstream activation of MEK. We are currently focusing on assessing various combination therapies with MEK inhibitors, such as RTK inhibitors or second generation RAF inhibitors to overcome the feedback effect and drug-induced enhanced RTK activity. We have observed synergy in some cases, such as with the BRAF inhibitor AZ628 and the MEK inhibitor PD-901 in the H1755 cell line carrying the BRAF[G469A] mutation. In other cases we have observed additive effects suggesting co-existing oncogenic signalling.

    Conclusion
    Our findings suggest that different combination therapies are effective in the various mutant-BRAF cell lines and efficacy may depend on co-existing oncogenic ‘drivers’ and compensatory signalling mechanisms. We predict that combination treatment strategies for effective responses in BRAF-mutant NSCLCs may need to be determined on a personalised basis following tumour characterisation for co-expression of additional activators of the MAPK signalling pathway.