GR cells are dependent upon sustained CDC25C signaling as pharmacologic or genetic inhibition of CDC25C induce synthetic lethality. GR cells are dependent.

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GR cells are dependent upon sustained CDC25C signaling as pharmacologic or genetic inhibition of CDC25C induce synthetic lethality. GR cells are dependent upon sustained CDC25C signaling as pharmacologic or genetic inhibition of CDC25C induce synthetic lethality. Percent viability of control and GR (A) H460 and (B) A549 cells after a 72 hours of treatment with the CDC25C inhibitors, NSC-663284 (0–10 μmol/L; left) and NSC-95397 (0–40 μmol/L; right) was determined by MTS assay and level of significance was determined performing unpaired t test on IC50 values obtained from three independent biological repeats and denoted as **, P < 0.01 and ***, P < 0.001. See Supplementary Table S3 for further details. C, CDC25C was silenced in KRAS-mutant H460 and A549 GR cells by expressing specific shRNA and percent viability was measured by MTS assays after 72 hours treatment with increasing concentrations of ganetespib. A549 or H460 GR cells expressing scramble shRNA (SCR) were used as a negative control. Bar graphs represent a comparative display of the respective dose response curves showing level of significance at 50 nmol/L and 100 nmol/L doses of ganetespib which were determined by performing unpaired t test between the groups (*, P < 0.05; **, P < 0.01; ***, P < 0.001). D, The combination of ganetespib and CDC25C inhibitor, NSC-663284 was assessed in A549, where cells were treated with increasing concentrations of ganetespib (0, 25, and 100 nmol/L) in absence or in presence of 1 μmol/L NSC-663284 for 48 hours followed by MTS assay to determine the percent viability of the cells. Bars represent the mean percent cell viability (± SD) relative to the mean of control cells (DMSO). Each cell type in each experiment included at least 4 replicates. Statistical significance by unpaired Student t test are denoted as *, P < 0.05; ***, P < 0.001. E,KRAS-mutant NSCLC PDX model. Athymic nude mice bearing the indicated tumors (n = 8 mice per group) were intravenously dosed with either vehicle or ganetespib (50 mg/kg) or NSC-663284 (3 mg/kg) or both. Data are presented as mean ± SD. Ganetespib vs. ganetespib + NSC-663284, **, P < 0.01; NSC-663284 versus ganetespib + NSC-663284, ****, P < 0.0001). Suman Chatterjee et al. Mol Cancer Ther 2017;16:1658-1668 ©2017 by American Association for Cancer Research