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: Yun-Tian Li, Xiao-Jun Qian, Yan Yu, Zhen-Hua Li, Rui-Yan Wu, Jiao Ji, Lin Jiao, Xuan Li, Peng-Fei Kong, Wen-Dan Chen, Gong-Kan Feng, Rong Deng, Xiao-Feng Zhu
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 19 Pg. 17491-500 (Jul 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26036637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Quinazolines
• Lapatinib
• Doxorubicin
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• CASP8 protein, human
• Caspase 8

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (metabolism)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• DNA Damage
• Doxorubicin (administration & dosage)
• ErbB Receptors (antagonists & inhibitors)
• Erlotinib Hydrochloride (administration & dosage)
• Humans
• Immunoprecipitation
• Lapatinib
• Protein Kinase Inhibitors (pharmacology)
• Protein Multimerization
• Quinazolines (administration & dosage)
• Transfection