Abstract. With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) in patients with advanced non-small cell lung cancer (NSCLC), acquired resistance has become a major clinical problem. A combination of different signaling pathway inhibitors is a promising strategy to overcome this. In the present study, the mitogen-activated protein kinase kinase 1/2 inhibitor, AZD6244, was used in combination with gefitinib to investigate the efficacy of this treatment in NSCLC cell lines, particularly in gefitinib-resistant cells. The EGFR-TKI-sensitive PC-9 (mutant EGFR/wild-type K-Ras) and EGFR-TKI-resistant A549 (wild-type EGFR/mutant K-Ras) human NSCLC cell lines were treated with AZD6244 alone, gefitinib alone or the combination of the two drugs, and the effects were evaluated using cell proliferation assays, with alterations in signaling pathways analyzed by western blotting. It was found that the growth inhibitory effect of combination treatment with gefitinib and AZD6244 was greater than that of gefitinib alone in the EGFR-TKI-resistant A549 cells. Treatment of A549 cells with gefitinib alone reduced the expression level of the activated form of Akt, and the combination of the two drugs showed stronger inhibition of phosphorylated-Akt and phosphorylated-extracellular signal-regulated kinases. The data showed that the combination of AZD6244 and gefitinib exhibited dose-dependent synergism in gefitinib-resistant NSCLC cells. Thus, a preclinical rationale exists for the use of AZD6244 to enhance the efficacy of gefitinib in patients with EGFR-TKI-resistant NSCLC.

Purpose: Cervical cancer is one of the leading causes of cancer death among women worldwide. Checkpoint kinase 1 (Chk1) has a critical role in DNA damage response and cell cycle checkpoint control. Emerging evidence suggests that Chk1 promotes tumor growth. However, whether Chk1 is important for development of cervical cancer is largely unknown. Methods: The levels of Chk1 mRNA expression were determined using quantitative real-time polymerase chain reaction in a panel of 90 cervical specimens, including 30 cervical cancer tissues, 30 CIN II–III, and 30 normal cervical tissues. We investigated the correlation between Chk1 and HPV16 E6/E7 at the mRNA level using another 30 CIN II–III and 32 cervical cancer tissues with HPV16 infection. MTT and cell cycle assays were conducted to show the function role of Chk1 in cervical cancer SiHa cells. Results: Chk1 was gradually increased during cervical lesion progression and positively correlated with HPV16 E6/E7 expression. Inhibition of Chk1 resulted in suppressed cell proliferation concomitant with the blocking of cell cycle at S-phase in cervical cancer SiHa cells. Conclusions: These results indicate that maintained Chk1 expression by HPV16 E6/E7 in cervical cancer cells promotes cell growth by blocking the cell cycle progression, and may point to novel strategies for targeting Chk1 in cancer therapy.