We analyzed the anti growth activity of combination therapy of PDGFR inhibitors and different AKIs, to help validate PDGFRA as a sensitizing target for AKIs in pancreatic cancer. Different concentrations of imatinib coupled with a dilution of two AKIs were first evaluated in three pancreatic cancer cell lines. As shown in Fig. AP26113 2, addition of 9 or 13 mM of imatinib to ZM447439 resulted in a shift of the dose?response curves in most 3 cell lines. Imatinib at 13 mM paid down the IC50 values of ZM447439 by 2 and 3 fold in the AsPC 1 and SU. 86. 86 cell lines, respectively. Improvement of imatinib to PHA 739358 also improved the awareness of two of the cell lines. Imatinib reduced the IC50 of PHA 739358 by 2 fold in AsPC 1 and 9 fold in SU. 86. 86. In addition to the IC50 reduction in the AsPC 1 cell line, the cytotoxicity effect was enhanced by this combination at the larger concentration of PHA 739358. Dining table 2 summarizes the IC50 values of the AKIs in mixture with imatinib after normalization with the imatinib only therapy and their percentages to the IC50 values of AKI only remedies in the three pancreatic cancer cell lines. A Papillary thyroid cancer rate of less than 1 indicates a synergistic relationship between the AKIs and imatinib at the levels tested. Since imatinib is known to inhibit other kinases besides PDGFR, to help concur that the synergism observed is certain to PDGFR inhibition we tested another known small molecule inhibitor of PDGFR, sorafenib. Similar to imatinib, sorafenib caused a shift of PHA 739358 dose?response curves in AsPC 1 and SU. 86. 86 cell lines however not in BxPC 3. Because Aurora kinase inhibition has demonstrated an ability to induce cell cycle arrest we examined the effects of the combination therapy of imatinib and PHA 739358 on cell cycle progression in AsPC 1 cells. As expected, PHA 739358 alone induced significant G2/M arrest and polyploidy. The G2/M population was increased by pha 739358 significantly order Imatinib from 19. 37% to 30. 56% and the populace of polyploidy cells from 5. 80% to 15. 61% within 24 h. Imatinib does not affect the cell cycle distribution of at 24 h. However, the combination treatment of both drugs resulted in further induction of G2/M arrest compared to PHA 739358 alone. Similar synergistic effect was seen at both 48 and 72 h time points where the combination treatment significantly improved G2/M charge when compared to either drug alone. Apparently, the improvement of imatinib to PHA 739358 paid off the polyploidy population induced by PHA 739358 at all 3 time points. For instance, at the 24 h time level, the cell population with 4N DNA increased from 5.8% in 5 and untreated control. 6% in imatinib only treatment to 15. Six months in PHA 739358 only therapy, and paid down back again to 5. Four weeks in the imatinib plus PHA 739358 combination treatment.