Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics (Plos Medicine, 2007, 4(10); e316:1681-1690)

報告日期: 2008/12/30
報告時間: 16:00/16:50
報告學生: 陳怡婷
講評老師: 王憶卿

Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant EGFR Requires BIM and Can Be Enhanced by BH3 Mimetics

Plos Medicine, 4(10), 1681-1690 (2007)


Speaker: Yi-Ting, Chen  (陳怡婷) 

Commentator: Dr. Yi-Ching, Wang  (王憶卿 老師)  

Date: 2008/12/30 16:00~16:50

Place: Room 602



Abnormality in EGF-EGFR signaling has been found in a broad range of cancer, including carcinomas of lung, breast, and colon. EGFR inhibitors such as gefitinib have been proved successfully to induce tumor cell death in a broad range of cancers, particularly non-small cell lung cancers (NSCLCs, the commonest type of lung cancer) harboring activating mutations within the EGFR gene. However, the molecular mechanisms that cause cancer cell death and tumor regression in response to gefitinib have not been fully understood. In this study, the authors found that gefitinib triggered intrinsic apoptosis signaling by activated BAX. Gefitinib also cause increase in the proapoptotic BH3-only protein BIM through both transcriptional and post-translational mechanisms. They further confirmed that BIM was essential for Gefitinib-induced apoptosis of NSCLC by using RNA interference. By using pharmacological inhibitors, the authors showed that MEK-ERK1/2 signaling but not PI3K, JNK, AKT was critical for BIM activation. In conclusion, these results proved that BIM was essential for gefitinib-induced killing of NSCLC cells expressing mutant EGFR. By co-treating cells with mimics BH3 compound enhanced gefitinib-induced killing of NSCLC cells. These data suggest that the treatment with the combination of gefitinib and BH3 mimetics, such as ABT-737, may be a potential therapy for NSCLC.



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