title: Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma.
abstract: Development of drug resistance limits the efficacy of targeted therapies. Alternative approaches using different combinations of therapeutic agents to inhibit several pathways could be a more effective strategy for treating cancer. The effects of the approved epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (gefitinib) or a multi-targeted kinase inhibitor (sorafenib) in combination with a histone deacetylase inhibitor (vorinostat) on cell proliferation, cell cycle distribution, apoptosis, and signaling pathway activation in human lung adenocarcinoma and hepatocarcinoma cells with wild-typeEGFRand mutantKRASwere investigated. The effects of the synergistic drug combinations were also studied in human lung adenocarcinoma and hepatocarcinoma cells in vivo. The combination of gefitinib and vorinostat synergistically reduced cell growth and strongly induced apoptosis through inhibition of the insulin-like growth factor-1 receptor/protein kinase B (IGF-1R/AKT)-dependent signaling pathway. Moreover, the gefitinib and vorinostat combination strongly inhibited tumor growth in mice with lung adenocarcinoma or hepatocarcinoma tumor xenografts. In contrast, the combination of sorafenib and vorinostat did not inhibit cell proliferation compared to a single treatment and induced G2/M cell cycle arrest without apoptosis. The sorafenib and vorinostat combination sustained the IGF-1R-, AKT-, and mitogen-activated protein kinase-dependent signaling pathways. These results showed that there was synergistic cytotoxicity when vorinostat was combined with gefitinib for both lung adenocarcinoma and hepatocarcinoma with mutantKRASin vitro and in vivo but that the combination of vorinostat with sorafenib did not show any benefit. These findings highlight the important role of the IGF-1R/AKT pathway in the resistance to targeted therapies and support the use of histone deacetylase inhibitors in combination with EGFR-tyrosine kinase inhibitors, especially for treating patients with mutantKRASresistant to other treatments.
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Jeannot
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France; Department of Biochemistry, Toxicology and Pharmacology, Grenoble University Hospital, Grenoble, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Busser
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Vanwonterghem
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Michallet
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Sana
authors.initials: S
authors.lastname: Ferroudj
authors.affiliation: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors.forename: Murat
authors.initials: M
authors.lastname: Cokol
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France; Faculty of Medicine, Dokuz Eyul University, Izmir Biomedicine and Genome Center, Izmir, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ozturk
authors.affiliation: INSERM U1209, Department Cancer Targets and Experimental Therapeutics, Grenoble, France; University Grenoble Alpes, Institute for Advanced Biosciences, Grenoble, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Hurbin
keywords: combined treatments; hepatocarcinoma; non-small cell lung cancer; targeted therapy