Crizotinib-resistant NPM-ALK mutants retain sensitivity to ganetespib.

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Crizotinib-resistant NPM-ALK mutants retain sensitivity to ganetespib. Crizotinib-resistant NPM-ALK mutants retain sensitivity to ganetespib. A, ganetespib and crizotinib sensitivity was assessed in crizotinib-sensitive NPM-ALK BaF3 cells and crizotinib-resistant NMP-ALK mutants. Relative IC50 values are plotted on the basis of the sensitivity of the parental NPM-ALK BaF3 line to each compound. Clinically relevant mutations in NSCLC are indicated by asterisks. B, dose–response analysis of ganetespib. Crizotinib-sensitive NPM-ALK/BaF3 cells (top left) together with NPM-ALK/BaF3 containing the indicated amino acid substitutions known to confer crizotinib resistance were incubated for 24 hours, with the range of ganetespib concentrations indicated, and the stability of the NPM-ALK protein expressed in each line was assessed by immunoblotting. C, kinetics of ganetespib-associated NPM-ALK protein degradation. The NPM-ALK protein degradation response of crizotinib-sensitive NPM-ALK/BaF3 and NPM-ALK/BaF3 containing the L1196M gatekeeper mutation to incubation in 250 nmol/L ganetespib for the indicated times is shown. Jim Sang et al. Cancer Discovery 2013;3:430-443 ©2013 by American Association for Cancer Research