title: EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging therapy.
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.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yun-Tian
authors.initials: YT
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.|Department of Oncology, Anhui Provincial Hospital, Affiliated to Anhui Medical University, Hefei, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Qian
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: The School of Medicine, Jinan University, Guangzhou, China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Rui-Yan
authors.initials: RY
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wen-Dan
authors.initials: WD
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000008:administration & dosage; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D006801:Humans; D047468:Immunoprecipitation; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055503:Protein Multimerization; D011799:Quinazolines / Q000008:administration & dosage; D014162:Transfection
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D004317:Doxorubicin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: EGFR inhibitors; breast cancer; caspase-8; doxorubicin; sequential application