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Molecular mechanism of the schedule-dependent synergistic interaction in EGFR-mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib.

ABSTRACT: Chemotherapy combined concurrently with TKIs produced a negative interaction and failed to improve survival when compared with chemotherapy or TKIs alone in the treatment of non-small cell lung cancer (NSCLC). The present study investigated the sequence-dependent interaction between paclitaxel and gefitinib and clarified the underlying mechanism.The effects on cell proliferation, EGFR signaling pathway, and TGF? expression were evaluated in a panel of human NSCLC cell lines harboring EGFR mutations with three different combination sequences: sequential treatment with paclitaxel followed by gefitinib (T?G), sequential treatment with gefitinib followed by paclitaxel (G?T), or concomitant treatment (T + G).The sequence-dependent anti-proliferative effects differed between EGFR-TKI-sensitive and -resistant cell lines carrying EGFR mutations. A synergistic anti-proliferative activity was obtained with paclitaxel treatment followed by gefitinib in all cell lines, with mean CI values of 0.63 in Hcc827, 0.54 in PC-9, 0.81 in PC-9/GR, and 0.77 in H1650 cells for the T?G sequence. The mean CI values for the G?T sequence were 1.29 in Hcc827, 1.16 in PC-9, 1.52 in PC-9/GR, and 1.5 in H1650 cells. The mean CI values for T+G concomitant treatment were 0.88 in Hcc827, 0.91 in PC-9, 1.05 in PC-9/GR, and 1.18 in H1650 cells. Paclitaxel produced a dose-dependent increase in EGFR phosphorylation. Paclitaxel significantly increased EGFR phosphorylation compared with that in untreated controls (mean differences: +50% in Hcc827, + 56% in PC-9, + 39% in PC-9/GR, and + 69% in H1650 cells; p < 0.05). The T?G sequence produced significantly greater inhibition of EGFR phosphorylation compared with the opposite sequence (mean differences: -58% in Hcc827, -38% in PC-9, -35% in PC-9/GR, and -30% in H1650 cells; p < 0.05). Addition of a neutralizing anti-TGF? antibody abolished paclitaxel-induced activation of the EGFR pathway in PC-9 and H1650 cells. Sequence-dependent TGF? expression and release are responsible for the sequence-dependent EGFR pathway modulation.The data suggest that the sequence of paclitaxel followed by gefitinib is an appropriate treatment combination for NSCLC cell lines harboring EGFR mutations. Our results provide molecular evidence to support clinical treatment strategies for patients with lung cancer.

SUBMITTER: Cheng H

PROVIDER: S-EPMC3035578 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Molecular mechanism of the schedule-dependent synergistic interaction in EGFR-mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib.

Cheng Hua H An She-Juan SJ Dong Song S Zhang Yi-Fang YF Zhang Xu-Chao XC Chen Zhi-Hong ZH Jian-Su Wu Yi-Long YL

Journal of hematology & oncology 20110121

<h4>Background</h4>Chemotherapy combined concurrently with TKIs produced a negative interaction and failed to improve survival when compared with chemotherapy or TKIs alone in the treatment of non-small cell lung cancer (NSCLC). The present study investigated the sequence-dependent interaction between paclitaxel and gefitinib and clarified the underlying mechanism.<h4>Methods</h4>The effects on cell proliferation, EGFR signaling pathway, and TGFα expression were evaluated in a panel of human NSC ...[more]

PMID: 21255411

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Project description:BackgroundThe epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs) harboring activating mutations within the EGFR gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms.Methods and findingsWe performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called "mitochondrial") apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome c, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11) through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK-ERK1/2 (mitogen-activated protein kinase kinase-extracellular signal-regulated protein kinase 1/2) signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase), JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8), or AKT (protein kinase B), was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737.ConclusionsInhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing activating mutations in the EGFR kinase domain, but the mechanisms of tumor cell killing are still unclear. In this paper, we demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR-MEK-ERK signaling cascade is critical for BIM activation. Moreover, we demonstrate that addition of a BH3 mimetic significantly enhances killing of NSCLC cells by the EGFR tyrosine kinase inhibitor gefitinib. It appears likely that this approach represents a paradigm shared by many, and perhaps all, oncogenic tyrosine kinases and suggests a powerful new strategy for cancer therapy.

Dataset Information

Molecular mechanism of the schedule-dependent synergistic interaction in EGFR-mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib.

Publications

Molecular mechanism of the schedule-dependent synergistic interaction in EGFR-mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib.

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