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P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Coordinates: 10/28/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
P1.05-012 - The HSP90 inhibitor, AT13387, displays single agent activity in erlotinib-sensitive and -resistant models of EGFR-activated NSCLC (ID 1791)
09:30 - 16:30 | Author(s): J. Lewis
Epidermal growth factor receptor (EGFR) is activated in subsets of non-small cell lung cancer (NSCLC) by mutations such as L858R and exon19 deletions. EGFR-tyrosine kinase inhibitors such as gefitinib and erlotinib have been successfully used to treat tumors with these mutations, but responses tend to be limited by the development of resistance, often through further mutations in EGFR such as T790M. EGFR and its mutated forms are clients of HSP90 and so dependent on this chaperone for their stability. HSP90 inhibition is therefore an alternative mechanism for targeting EGFR-driven disease, which should be effective on EGFR inhibitor-sensitive or -resistant disease alike. AT13387 is a novel, potent, fragment-derived HSP90 inhibitor and is the subject of a number of Phase II clinical trials, including one in NSCLC.
The activity of AT13387 was investigated in vitro and in vivo in erlotinib-sensitive and -resistant EGFR-activated NSCLC cell lines and mouse xenograft models (see Table). The HCC827R cell line was generated by prolonged incubation of HCC827 cells with erlotinib. Cell proliferation was measured by Alamar blue assay. Protein levels were determined by western blotting.
AT13387 was tested in a panel of EGFR-driven NSCLC cell lines and potently inhibited proliferation of both erlotinib-sensitive and -resistant cells including a cell line with acquired erlotinib resistance (HCC827R) (see Table).
Inhibition of proliferation of EGFR-dependent NSCLC cell linesTreatment of both erlotinib-sensitive and -resistant cell lines with AT13387 resulted in depletion of EGFR and its phospho-form, irrespective of its mutation status (L858R, T790M, Exon19 deletion). Other clients such as AKT were also depleted. A decrease in the levels of phospho-ERK and phospho-S6 indicated that EGFR signalling was also being inhibited in both erlotinib-sensitive and -resistant cells. In vivo, AT13387 significantly inhibited tumor growth in EGFR-driven tumor xenograft models (HCC827, NCI-H1975) when administered at 70 mg/kg ip once weekly. As expected, erlotinib dosed at 12.5 mg/kg once daily caused regression in HCC827 xenografts, whilst 75 mg/kg once daily had no effect on tumor growth in the resistant NCI-H1975 model. Levels of EGFR and phospho-EGFR were depleted for up to 72 hours in xenograft tumors treated with a single dose of 70 mg/kg AT13387, whilst a reduction in phospho-ERK and phospho-S6 again demonstrated an inhibition of signalling.
Cell line EGFR mutation status Erlotinib inhibition of proliferation IC50 (nM) AT13387 inhibition of proliferation IC50 (nM) HCC827 Exon19 Del 57 33 NCI-H1650 Exon19 Del > 10 000 54 NCI-H1975 L858R/T790M > 10 000 30 H820 Exon19 Del/T790M > 10 000 70 HCC827R N/D > 10 000 26
AT13387 was shown to be effective in erlotinib-sensitive and -resistant NSCLC models, depleting levels of EGFR regardless of its mutation status. These data suggest that AT13387 treatment may also be a potential approach for combating EGFR inhibitor resistance in the clinic.