title: A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib.
abstract: Non-small cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) responds to EGFR tyrosine kinase inhibitors such as erlotinib. However, secondary somatic EGFR mutations (e.g., T790M) confer resistance to erlotinib. BMS-690514, a novel panHER/vascular endothelial growth factor receptor (VEGFR) inhibitor described here, exerted antiproliferative and proapoptotic effects on NSCLC cell lines, with prominent efficacy on H1975 cells expressing the T790M mutation. In this model, BMS-690514 induced a G(1) cell cycle arrest, as well as ultrastructural hallmarks of apoptosis, mitochondrial release of cytochrome c, and activation of caspases involved in the intrinsic (e.g., caspase-2, caspase-3, caspase-7, and caspase-9), but not in the extrinsic (e.g., caspase-8), pathway. Caspase inhibition conferred partial protection against BMS-690514 cytotoxicity, pointing to the involvement of both caspase-dependent and caspase-independent effector mechanisms. Transcriptome analyses revealed the up-regulation of proapoptotic (e.g., Bim, Puma) and cell cycle inhibitory (e.g., p27(Kip1), p57(Kip2)) factors, as well as the down-regulation of antiapoptotic (e.g., Mcl1), heat shock (e.g., HSP40, HSP70, HSP90), and cell cycle promoting [e.g., cyclins B1, D1, and D3; cyclin-dependent kinase 1 (CDK1); MCM family proteins; proliferating cell nuclear antigen (PCNA)] proteins. BMS-690514-induced death of H1975 cells was modified in a unique fashion by a panel of small interfering RNAs targeting apoptosis modulators. Down-regulation of components of the nuclear factor-kappaB survival pathway (e.g., p65, Nemo/IKK gamma, TAB2) sensitized cells to BMS-690514, whereas knockdown of proapoptotic factors (e.g., Puma, Bax, Bak, caspase-2, etc.) and DNA damage-related proteins (e.g., ERCC1, hTERT) exerted cytoprotective effects. BMS-690514 is a new pan-HER/VEGFR inhibitor that may become an alternative to erlotinib for the treatment of NSCLC.
authors.affiliation: INSERM, U848, Villejuif, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: de La Motte Rouge
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
authors.forename: Ken A
authors.initials: KA
authors.lastname: Olaussen
authors.forename: Yael
authors.initials: Y
authors.lastname: Zermati
authors.forename: Ezgi
authors.initials: E
authors.lastname: Tasdemir
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.forename: Hugues
authors.initials: H
authors.lastname: Ripoche
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Francis
authors.initials: F
authors.lastname: Harper
authors.forename: Gerard
authors.initials: G
authors.lastname: Pierron
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pinna
authors.forename: Natalia
authors.initials: N
authors.lastname: Araujo
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Belan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
authors.forename: Tai Wai
authors.initials: TW
authors.lastname: Wong
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D040081:Protein Array Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor