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The antitumor effect of orally active heat shock protein 90 Inhibitor, 17-DMAG, on the growth of gefitinib-resistant non-small cell lung cancer.

e22064 Background: It has been reported that NSCLC cell lines with activating mutations of EGFRgene were significantly sensitive to Heat Shock Protein 90 (Hsp 90 ) ihibitors regardless of the secondary T790M mutation.


METHODS
We examined the antitumor effect of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), the orally active Hsp90 inhibitor, on the growth of NSCLC cell lines in vitro and in vivo.


RESULTS
In MTS assay, the IC50 values for 3 cell lines with EGFR mutation (PC-9, RPC-9, and NCI-H1975) ranged from 0.15 to 0.28 μM. RPC-9 is a gefitinib-resistant lung cancer cell line with the secondary T790M mutation established from PC-9. By contrast, those of 7 EGFR-wild type cell lines ranged from 1.63 to 28.5 μM. Western blot analysis revealed that mutant EGFRs were more readily depleted than wild-type EGFRs after the treatment of 17-DMAG. Furthermore, expression of phospho-Akt, phospho-MAPK, cdk4, and cyclin D1 was depleted after exposure to low concentrations of 17-DMAG in EGFR-mutant cells. Celeaved PARP expression confirmed apoptosis in response to 17-DMAG in EGFR-mutant cells. In animal models, 17-DMAG significantly reduced the growth of EGFR-mutant cell lines PC-9 and RPC-9 compared with controls and induced degradation of mutant EGFR. In contrast, 17-DMAG did not inhibit the growth of EGFR wild type cell lines compared with controls.


CONCLUSIONS
These results suggested that 17-DMAG could become a novel therapeutic agent for patients with lung tumors expressing mutant EGFR and having developed clinical resistance to gefitinib. No significant financial relationships to disclose.