EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging therapy

// Yun-Tian Li 1,* , Xiao-Jun Qian 1,2,* , Yan Yu 1,* , Zhen-Hua Li 3 , Rui-Yan Wu 1 , Jiao Ji 1 , Lin Jiao 1 , Xuan Li 1 , Peng-Fei Kong 1 , Wen-Dan Chen 1 , Gong-Kan Feng 1 , Rong Deng 1 and Xiao-Feng Zhu 1 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 Correspondence to: 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 Abstract 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.