title: Sequential use of vinorelbine followed by gefitinib enhances the antitumor effect in NSCLC cell lines poorly responsive to reversible EGFR tyrosine kinase inhibitors.
abstract: Preclinical studies have suggested that combining cytotoxic agents with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat EGFR-mutated tumors may increase their inhibitory effect depending on the order of drug administration. The antitumor efficacy of different treatment sequences using vinorelbine (VNB) and gefitinib (GEF) was investigated both in vitro and in vivo in non-small cell lung cancer (NSCLC) cell lines with the rationale of potentially translating these findings into the clinical setting. The EGFR-wild-type A549 and the EGFR-mutated (exon 21 L858R/exon 20 T790M) H1975 cell lines were treated as follows: GEF followed by VNB, VNB followed by GEF and the two drugs applied individually or concurrently. Results in vitro demonstrated that the sequence of VNB followed by GEF was significantly more active than single-agent treatments. The expression of activated EGFR and its downstream pathway genes indicated that the increased cytotoxic effect of the VNB and GEF treatment sequence was accompanied by inhibition of EGFR, AKT and ERK1/2. Moreover, the increased inhibition of tumor growth after treatment with VNB followed by GEF was also confirmed in CD1-nude mice that were xenotransplanted with H1975 cells (p < 0.0001). This effect was paralleled by a corresponding decrease in cancer glucose consumption, as assessed by micro-positron emission tomography scans (p < 0.05). These preclinical findings in NSCLC cell lines, which are poorly responsive to EGFR-TKIs, demonstrated that the sequential treatment of VNB followed by GEF induced a significant antitumor effect, which supports the translation of this treatment schedule into a clinical setting.
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Dal Bello
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Alama
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Barletta
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Coco
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.|Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa-IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Truini
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Vanni
authors.affiliation: Pathology and Cytohistology Division, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Boccardo
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Genova
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rijavec
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Biello
authors.affiliation: Nuclear Medicine Unit, Department of Health Science, University of Genoa-IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bottoni
authors.affiliation: Nuclear Medicine Unit, Department of Health Science, University of Genoa-IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Sambuceti
authors.affiliation: Lung Cancer Unit, IRCCS AOU San Martino-IST-National Institute for Cancer Research, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grossi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015398:Signal Transduction; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D014747:Vinblastine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077235:Vinorelbine; D000077156:Gefitinib
keywords: NSCLC; TKI resistance; gefitinib; vinorelbine