Schedule-dependent antitumor activity of the combination with erlotinib and docetaxel in human non-small cell lung cancer cells with EGFR mutation, KRAS mutation or both wild-type EGFR and KRAS

Abstract

Abstract. Erlotinib is used as a standard treatment for recurrent advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations in NSCLC have been shown to be a predictive factor of erlotinib, although the relationship between K-ras oncogene (KRAS) mutations and erlotinib resistance is controversial. Recently, in vitro sequence-dependent interactions of erlotinib and docetaxel have been studied on as a novel therapeutic approach against NSCLC. The purpose of the present study was to determine the optimum novel regimen of erlotinib and docetaxel against NSCLC cells which have EGFR mutation (HCC827 cells), KRAS mutation (A549 cells) or both wild-type (NCI-H292 cells). First, we analyzed the effects of in vitro combination for cell proliferation-inhibition using a combination index. In all cell lines, docetaxel followed by erlotinib treatment showed nearly additive effects. On the other hand, erlotinib followed by docetaxel treatment showed remarkable antagonistic interactions. Second, we examined the effect of combinations on the in vitro apoptosis induction. Erlotinib followed by docetaxel treatment reduced apoptosis induction compared with docetaxel alone; in contrast, docetaxel followed by erlotinib treatment had no inhibitory effects on docetaxelinduced apoptosis in any of the cell lines. Finally, an in vivo tumor growth inhibition test was performed using xenograft models. Docetaxel followed by erlotinib administration resulted in significant tumor growth inhibition compared with erlotinib or docetaxel monotherapy in all models. In conclusion, we demonstrated that docetaxel followed by erlotinib therapy was a potentially optimum regimen against NSCLC regardless of the mutation status of EGFR and KRAS.

Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non–small lung cancer with EGFR TKIs-resistant mutation

“…The mechanism of antagonism observed with concurrent administration of EGFR TKIs and chemotherapy is relevant to pharmacodynamic separation, since G1-phase arrest primarily induced by EGFR TKIs in NSCLC possibly interferes with the cell cycle-specific cytotoxicity of chemotherapy (Davies et al 2006). At present, a new approach involving the sequential combination of EGFR TKI and chemotherapy that has been shown to hinder the antagonistic effects of concomitant administration is being investigated in NSCLC and other cancers (Furugaki et al 2010;Saigal et al 2008). However, there is little in vitro or in vivo research examining sequential combinations of sunitinib and chemotherapy.…”

Dependence on the MUC1-C Oncoprotein in Non–Small Cell Lung Cancer Cells

“…Human H1975 (35), H1650 (ATCC) (36), HCC827 (35), A549, H2228 (13), H460 (37), H1299 (38) and NCI-H292 (39) NSCLC cells were all obtained from the ATCC and passaged for less than 6 months and then replaced with early passage frozen stocks. No further authentication was performed.…”

Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by down-regulating TIGAR expression and depleting NADPH

“…20 TIGAR-specific primers (5Ј-CTCCAGTGATCTCATGAG-3Ј and 5Ј-AGACACTGGCT-GCTAATC-3Ј). 26 RNA-specific primers for human ␤-actin were used for the control. 20 The RNA was reverse transcribed and amplified using SuperScript One-Step RT-PCR with Platinum Taq (Invitrogen).…”