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. Author manuscript; available in PMC: 2018 Aug 1.
Published in final edited form as: Mol Cancer Ther. 2017 May 31;16(8):1658–1668. doi: 10.1158/1535-7163.MCT-17-0114

Figure 5. GR cells are dependent upon sustained CDC25C signaling as pharmacologic or genetic inhibition of CDC25C induce synthetic lethality.

Figure 5

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 µM) (left) and NSC-95397 (0 – 40 µM) (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 nM and 100 nM 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 nM) in absence or in presence of 1 µM 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, and ****, p < 0.0001(E) KRAS mutant NSCLC PDX model. Athymic nude mice bearing the indicated tumors (n = 8 mice per group) were i.v. 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 vs. Ganetespib + NSC-663284, ****, p < 0.0001).