dehydroxymethylepoxyquinomicin and Lung-Neoplasms

Although nuclear factor (NF)-κB and phosphoinositide 3-kinase (PI3K)-Akt-mTOR comprise key pathways, their interrelationship in lung cancer cell survival is poorly understood and needs further analyses.. We examined the activation of the NF-κB and Akt-mTORC1-p70 S6 kinase (S6K) pathways and the effect of inhibitors for NF-κB, mTORC1, and Akt using fresh lung adenocarcinoma cells.. The cases used for this study showed constitutive NF-κB activity; however, all cases but one showed resistance to NF-κB inhibition. Further examination revealed that the resistant cases were also active in the Akt-mTORC1-S6K pathway. These cases were insensitive to mTORC1 inhibition but sensitive to Akt inhibition. Akt inhibition recovered sensitivity to NF-κB inhibition and dual inhibition showed a synergistic effect on apoptosis induction.. These results indicate that the activation of Akt involves resistance to NF-κB inhibition and both pathways synergistically support the survival of lung adenocarcinoma cells. The results also indicate that inhibition of the mTORC1-S6K pathway does not inhibit the survival of these cells.

Topics: Adenocarcinoma; Aged; Apoptosis; Benzamides; Cell Survival; Cells, Cultured; Cyclohexanones; Drug Synergism; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Lung Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Multiprotein Complexes; Neoplasm Staging; NF-kappa B; Oncogene Protein v-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Tetrazoles; TOR Serine-Threonine Kinases

Chemoresistance is a major therapeutic challenge to overcome in NSCLC, in order to improve the current survival rates of<15% at 5 years. We and others have shown increased PI3K signaling in NSCLC to be associated with a more aggressive disease, and a poorer prognosis. In this study, targeted inhibition of three strategic points of the PI3K-NFκB axis was performed with the aim of exploiting vulnerabilities in cisplatin-resistant NSCLC cells. Cisplatin-resistant cell lines were previously generated through prolonged exposure to the drug. Expression of PI3K and NFκB pathway-related genes were compared between cisplatin-resistant cells and their matched parent cells using a gene expression array, qRT-PCR, DNA sequencing, western blot, and immunofluorescence. Targeted inhibition was performed using GDC-0980, a dual PI3K-mTOR inhibitor currently in Phase II clinical trials in NSCLC, and DHMEQ, an inhibitor of NFκB translocation which has been used extensively both in vitro and in vivo. Effects of the two inhibitors were assessed by BrdU proliferation assay and multiparameter viability assay. NFKBIA was shown to be 12-fold overexpressed in cisplatin-resistant cells, with no mutations present in exons 3, 4, or 5 of the gene. Corresponding overexpression of IκBα was also observed. Treatment with DHMEQ (but not GDC-0980) led to significantly enhanced effects on viability and proliferation in cisplatin-resistant cells compared with parent cells. We conclude that NFκB inhibition represents a more promising strategy than PI3K-mTOR inhibition for treatment in the chemoresistance setting in NSCLC.

Topics: Antineoplastic Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Cyclohexanones; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrimidines; Transcriptome