In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1051-1051
Abstract:
EGFR tyrosine kinase inhibitors (TKIs) have demonstrated exciting results and led to advanced therapy trials in combination with chemotherapy. However, clinical studies have raised an important question why the antagonism between TKI and chemotherapy occurs in lung cancer patients only with wildtype but not mutant EGFR. In this study, we further explored the mechanism through which gefitinib gives rise to the negative effects when combined with cisplatin in wildtype EGFR lung cancer cells. We found that gefitinib inhibited cisplatin-induced caspase-independent cell death (CID) but not caspase-dependent cell death (apoptosis). In wildtype EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis and therefore compromising the efficacy of cisplatin. Moreover, inhibition of the EGFR/ERK/AKT pathway by gefinitib activated FOXO3a and subsequently reduced reactive oxygen species (ROS) induced by cisplatin treatment and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, which are known to induce ROS-mediated CID, strongly enhanced the effect of cisplatin in wildtype EGFR cells. Taken together, our findings provide a possible explanation for the previously failed clinical trials as well as a novel insight into future cancer therapy. Citation Format: Hirohito Yamaguchi, Jennifer L. Hsu, Chun-Te Chen, Ying-Nai Wang, Ming-Chuan Hsu, Shih-Shin Chang, Yi Du, How-Wen Ko, Roy S. Herbst, Mien-Chie Hung. EGFR inhibitors attenuate caspase-independent cell death and confer negative effects on cisplatin . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1051. doi:10.1158/1538-7445.AM2013-1051
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-1051
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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