Schedule-Dependent Apoptosis in K-ras Mutant Non–Small-Cell Lung Cancer Cell Lines Treated with Docetaxel and Erlotinib: Rationale for Pharmacodynamic Separation

Mahaffey, Christopher M.; Davies, Angela M.; Lara, Jr Primo N.; Pryde, B. J.; Holland, William; Mack, Philip C.; Gumerlock, Paul H.; Gandara, David R.

doi:10.3816/clc.2007.n.041

Cited by 71 publications

(53 citation statements)

References 12 publications

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“…Recently, the sequence-specific interactions of erlotinib and chemotherapeutic drug combinations were found to influence the efficacy of regimens in NSCLC (23). The treatment schedule of erlotinib and gemcitabine also affects the combination effects.…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity of erlotinib in combination with gemcitabine in in vitro and in vivo models of KRAS-mutated pancreatic cancers

Furugaki¹,

Iwai²,

Kondoh³

et al. 2010

Oncology Letters

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Abstract. Erlotinib treatment in combination with gemcitabine is a standard therapy for patients with locally advanced pancreatic cancer in many countries, including the US and the EU. Since mutations of the K-ras oncogene (KRAS) occur in approximately 90% of pancreatic cancers, we examined the antitumor activity of erlotinib in combination with gemcitabine in KRAS-mutated pancreatic cancer cell lines, HPAC and Capan-1, which have the KRAS mutation G12D and G12V, respectively. We analyzed the mode of inhibition of in vitro tumor cell proliferation by means of a combination index and found that a combination treatment of erlotinib plus gemcitabine had an additive effect in the two cell lines. We then examined the effect of erlotinib and gemcitabine on the phosphorylation of epidermal growth factor receptor (EGFR). Erlotinib strongly suppressed, while gemcitabine augmented the phosphorylation of EGFR, which was completely blocked by erlotinib in the two cell lines. An in vivo tumor growth inhibition test was then performed using the HPAC tumor xenograft model. The combination therapy of erlotinib and gemcitabine resulted in a significant inhibition of tumor growth compared with erlotinib or gemcitabine monotherapy. To the best of our knowledge, this is the first study to show the combination effect of erlotinib and gemcitabine in vivo using a xenograft model of a KRASmutated pancreatic cancer cell line.

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Section: Discussionmentioning

confidence: 99%

Antitumor activity of erlotinib in combination with gemcitabine in in vitro and in vivo models of KRAS-mutated pancreatic cancers

Furugaki¹,

Iwai²,

Kondoh³

et al. 2010

Oncology Letters

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“…Thus, a conclusion on the association between KRAS mutations and erlotinib resistance has not been reached even now. Sequential treatment of EGFR TKI and paclitaxel or docetaxel has been reported as a promising therapeutic approach against NSCLC, which indicates that pharmacodynamic separation is important for effective interactions of the two drugs (10,11). However, there is no evidence on the relativity between sequence-dependent interactions of these two drugs and EGFR or KRAS mutation status in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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

Furugaki¹

2010

Oncol Rep

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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.

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“…Furthermore, there is growing laboratory evidence of a possible sequence-dependent antagonism between EGFR-TKIs and cytotoxic agents as a result of the well-known G 1 -phase arrest of tumor cells by EGFR-TKIs, which protect tumor cells from cell cycle-specific cytotoxic agents (13,14). In the present study, flow cytometry demonstrated that both pemetrexed and erlotinib caused an accumulation of cells in the S and G 1 phases, respectively.…”

Section: Discussionmentioning

confidence: 56%

Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in BXPC-3 and PANC-1 human pancreatic cancer cells

Wang

Zhu

Zhang

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Previous studies have shown that both pemetrexed, a cytotoxic drug, and erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), inhibit the cell growth of pancreatic cancer cells. However, whether they exert a synergistic antitumor effect on pancreatic cancer cells remains unknown. The present study aimed to assess the synergistic effect of erlotinib in combination with pemetrexed using different sequential administration schedules on the proliferation of human pancreatic cancer BXPC-3 and PANC-1 cells and to probe its cellular mechanism. The EGFR and K-ras gene mutation status was examined by quantitative PCR high-resolution melting (qPCR-HRM) analysis. BXPC-3 and PANC-1 cells were incubated with pemetrexed and erlotinib using different administration schedules. MTT assay was used to determine cytotoxicity, and cell cycle distribution was determined by flow cytometry. The expression and phosphorylation of EGFR, HER3, AKT and MET were determined using Western blotting. Both pemetrexed and erlotinib inhibited the proliferation of BXPC-3 and PANC-1 cells in a dose-and time-dependent manner in vitro. Synergistic effects on cell proliferation were observed when pemetrexed was used in combination with erlotinib. The degree of the synergistic effects depended on the administration sequence, which was most obvious when erlotinib was sequentially administered at 24-h interval following pemetrexed. Cell cycle studies revealed that pemetrexed induced S arrest and erlotinib induced G 0 /G 1 arrest. The sequential administration of erlotinib following pemetrexed induced S arrest. Western blot analyses showed that pemetrexed increased and erlotinib decreased the phosphorylation of EGFR, HER3 and AKT, respectively. However, both pemetrexed and erlotinib exerted no significant effects on the phosphorylation of c-MET. The phosphorylation of EGFR, HER3 and AKT was significantly suppressed by scheduled incubation with pemetrexed followed by erlotinib, but not by concomitant or sequential incubation with erlotinib followed by pemetrexed. In summary, our results demonstrated that the combined use of erlotinib and pemetrexed exhibited a strong synergism in BXPC-3 and PANC-1 cells. The inhibitory effects were strongest after sequential administration of pemetrexed followed by erlotinib. The synergistic effects may be related to activation of the EGFR/HER3/AKT pathway induced by pemetrexed.

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Schedule-Dependent Apoptosis in K-ras Mutant Non–Small-Cell Lung Cancer Cell Lines Treated with Docetaxel and Erlotinib: Rationale for Pharmacodynamic Separation

Cited by 71 publications

References 12 publications

Antitumor activity of erlotinib in combination with gemcitabine in in vitro and in vivo models of KRAS-mutated pancreatic cancers

Antitumor activity of erlotinib in combination with gemcitabine in in vitro and in vivo models of KRAS-mutated pancreatic cancers

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

Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in BXPC-3 and PANC-1 human pancreatic cancer cells

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