taxane and Carcinogenesis

Chemotherapy is one of the methods to treat patients with non-small cell lung cancer (NSCLC) developing resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib. Previous studies revealed that the sensitivity to chemotherapy may depend on different cellular mechanisms of acquired EGFR-TKIs resistance. Thus, the present study aimed to investigate the sensitivity of distinct gefitinib-resistant NSCLC cell lines to chemotherapy in order to help select effective treatment regimens for patients with EGFR-TKI resistance. In the present study, we established two gefitinib-resistant cell lines (PC-9/ZD and PC-9/GR) with the human lung adenocarcinoma cell line PC-9 (carrying the delE746-A750 mutation in the EGFR gene). PC-9/ZD cell line expressed the T790M mutation, while PC-9/GR presented the phenotypes of epithelial to mesenchymal transition (EMT). PC-9/ZD cells were more sensitive to paclitaxel and docetaxel than PC-9 cells and knockdown of T790M decreased this sensitivity. In addition, PC-9/GR cells were less sensitive to chemotherapeutic drugs tested, including cisplatin, gemcitabine, pemetrexed, paclitaxel and docetaxel, compared to PC-9 and PC-9/ZD cells. CDH1 transfection reversed the EMT and restored the sensitivity to chemotherapy in PC-9/GR cells. Furthermore, PC-9 cells became resistant to chemotherapy after TGF-β1-induced EMT. The EMT in NSCLC cells significantly increased cancer stem cell (CSC) properties and tumorgenicity. Collectively, the present study revealed that gefitinib-resistant NSCLC cells carrying the T790M mutation were sensitive to taxane chemotherapy, indicating that T790M is a useful biomarker for the selection of chemotherapy. EMT in NSCLC cells confers resistance to chemotherapy, which may be associated with enhanced CSC properties.

Topics: Biomarkers, Tumor; Bridged-Ring Compounds; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Docetaxel; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; ErbB Receptors; Gefitinib; Gene Knockdown Techniques; Humans; Mutation; Neoplastic Stem Cells; Paclitaxel; Protein Kinase Inhibitors; Quinazolines; Taxoids

Palmitate, the enzymatic product of FASN, and palmitate-derived lipids support cell metabolism, membrane architecture, protein localization, and intracellular signaling. Tubulins are among many proteins that are modified post-translationally by acylation with palmitate. We show that FASN inhibition with TVB-3166 or TVB-3664 significantly reduces tubulin palmitoylation and mRNA expression. Disrupted microtubule organization in tumor cells is an additional consequence of FASN inhibition. FASN inhibition combined with taxane treatment enhances inhibition of in vitro tumor cell growth compared to treatment with either agent alone. In lung, ovarian, prostate, and pancreatic tumor xenograft studies, FASN inhibition and paclitaxel or docetaxel combine to inhibit xenograft tumor growth with significantly enhanced anti-tumor activity. Tumor regression was observed in 3 of 6 tumor xenograft models. FASN inhibition does not affect cellular taxane concentration in vitro. Our data suggest a mechanism of enhanced anti-tumor activity of the FASN and taxane drug combination that includes inhibition of tubulin palmitoylation and disruption of microtubule organization in tumor cells, as well as a sensitization of tumor cells to FASN inhibition-mediated effects that include gene expression changes and inhibition of β-catenin. Together, the results strongly support investigation of combined FASN inhibition and taxane treatment as a therapy for a variety of human cancers.

Topics: A549 Cells; Animals; Antineoplastic Agents; Azetidines; beta Catenin; Blotting, Western; Bridged-Ring Compounds; Carcinogenesis; Cell Line; Cell Line, Tumor; Enzyme Inhibitors; Fatty Acid Synthase, Type I; Female; Gene Expression Regulation, Neoplastic; Humans; Lipoylation; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Confocal; Microtubules; Molecular Structure; Nitriles; Phosphorylation; Pyrazoles; Reverse Transcriptase Polymerase Chain Reaction; Taxoids; Tubulin; Xenograft Model Antitumor Assays

Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.

Topics: Animals; Antigens, CD; Antineoplastic Agents; Bridged-Ring Compounds; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Humans; Membrane Microdomains; Mice, Inbred BALB C; Models, Biological; Neoplasms; Neoplastic Stem Cells; Phenotype; Protein Kinase Inhibitors; Signal Transduction; Taxoids; Time Factors