EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging therapy
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Yun-Tian Li1,*, Xiao-Jun Qian1,2,*, Yan Yu1,*, Zhen-Hua Li3, Rui-Yan Wu1, Jiao Ji1, Lin Jiao1, Xuan Li1, Peng-Fei Kong1, Wen-Dan Chen1, Gong-Kan Feng1, Rong Deng1 and Xiao-Feng Zhu1
1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China
2 Department of Oncology, Anhui Provincial Hospital, Affiliated to Anhui Medical University, Hefei, China
3 The School of Medicine, Jinan University, Guangzhou, China
* These authors have contributed equally to this work
Xiao-Feng Zhu, email:
Keywords: EGFR inhibitors, doxorubicin, breast cancer, caspase-8, sequential application
Received: February 11, 2015 Accepted: April 09, 2015 Published: April 29, 2015
The combination of time and order-dependent chemotherapeutic strategies has demonstrated enhanced efficacy in killing cancer cells while minimizing adverse effects. However, the precise mechanism remains elusive. Our results showed that pre-treatment of MCF-7 and MDA-MB-468 cells with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or lapatinib significantly enhanced the cytotoxic effects of DNA-damaging agents compared to coadministration of the EGFR inhibitor and DNA-damaging agent. Sequential application of erlotinib and doxorubicin increased activated caspase-8 by promoting pro-caspase-8 homodimerization and autocatalytical cleavage, whereas coadministration did not. We found that EGFR inhibitors promoted pro-caspase-8 homodimerization by inhibiting ERK pathway signaling, while doxorubicin promoted it. Our data highlight that ERK has the potential to inhibit the formation of pro-caspase-8 homodimers by phosphorylating pro-caspase-8 at S387. In conclusion, the pretreatment of EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging agents. Our findings provide rationale for novel strategies for the implementation of combined targeted and cytotoxic chemotherapy within a new framework of time and order-dependent therapy.
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