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: Thibault de La Motte Rouge, Lorenzo Galluzzi, Ken A Olaussen, Yael Zermati, Ezgi Tasdemir, Thomas Robert, Hugues Ripoche, Vladimir Lazar, Philippe Dessen, Francis Harper, Gerard Pierron, Guillaume Pinna, Natalia Araujo, Annick Harel-Belan, Jean-Pierre Armand, Tai Wai Wong, Jean Charles Soria, Guido Kroemer
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 13 Pg. 6253-62 (Jul 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17616683 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Quinazolines
• RNA, Small Interfering
• Erlotinib Hydrochloride
• ErbB Receptors
• Receptors, Vascular Endothelial Growth Factor

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology)
• Cell Cycle
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (metabolism, pathology)
• Protein Array Analysis
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• RNA, Small Interfering (metabolism)
• Receptors, Vascular Endothelial Growth Factor (metabolism)