title: Strategic targeting of the PI3K-NFκB axis in cisplatin-resistant NSCLC.
abstract: 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.
authors.affiliation: Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
authors.forename: Susan
authors.initials: S
authors.lastname: Heavey
authors.affiliation: Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
authors.forename: Peter
authors.initials: P
authors.lastname: Godwin
authors.affiliation: Cancer & Ageing Research Program; Queensland University of Technology; Brisbane, QLD Australia.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Baird
authors.affiliation: Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Barr
authors.affiliation: Department of Molecular Target Medicine; Aichi Medical University; Nagakute, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.affiliation: Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
authors.forename: Sinéad
authors.initials: S
authors.lastname: Cuffe
authors.affiliation: Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Finn
authors.affiliation: Cancer & Ageing Research Program; Queensland University of Technology; Brisbane, QLD Australia.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.affiliation: Thoracic Oncology Research Group; Institute of Molecular Medicine; Trinity Centre for Health Sciences; St. James's Hospital; Dublin, Ireland.
authors.forename: Kathy
authors.initials: K
authors.lastname: Gately
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism*; D003512:Cyclohexanones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002945:Cisplatin; D003512:Cyclohexanones; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C464444:dehydroxymethylepoxyquinomicin
keywords: A549; DHMEQ; GDC-0980; H460; chemoresistance; chemotherapy; drug resistance; lung cancer; non-small cell lung cancer