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A Novel Epidermal Growth Factor Receptor Inhibitor Promotes Apoptosis in Non–Small Cell Lung Cancer Cells Resistant to Erlotinib

¹ INSERM, U848; ² Institut Gustave Roussy; ³ Faculté de Médecine-Université Paris-Sud XI; ⁴ Institut Gustave Roussy, Unité de Génomique Fonctionnelle et Bioinformatique; ⁵ Institut Gustave Roussy, IFR54; ⁶ Institut Gustave Roussy, CNRS FRE2939; ⁷ Institut André Lwoff, FRE2937, Laboratoire Réplication de l'ADN et Ultrastructure du Noyau; ⁸ CNRS FRE 2944, Laboratoire Epigénétique et Cancer-Institut André Lwoff; ⁹ Institut Gustave Roussy, Département de Médecine, Villejuif, France; and ¹⁰ Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey

Requests for reprints: Guido Kroemer, INSERM U848, Institut Gustave Roussy, PR1, 39 rue Camille Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-60-46; Fax 33-1-42-11-60-47; E-mail: kroemer{at}igr.fr.

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 G₁ 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-B survival pathway (e.g., p65, Nemo/IKK, 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. [Cancer Res 2007;67(13):6253–62]

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