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Cancer Lett. 2016 Nov 1;382(1):32-43. doi: 10.1016/j.canlet.2016.08.022. Epub 2016 Aug 26.

Broad RTK-targeted therapy overcomes molecular heterogeneity-driven resistance to cetuximab via vectored immunoprophylaxis in colorectal cancer.

Author information

1
Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. Electronic address: hus@smmu.edu.cn.
2
Department of Anesthesiology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing 210002, China.
3
Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China.
4
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
5
Department of Emergency Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
6
Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
7
Molecular Drug Discovery Center, Fengchao Medical Technology (Shanghai) Co. Ltd., Shanghai, 200235, China.
8
Department of Biophysics, College of Basic Medical Sciences, Second Military Medical University, Shanghai 200433, China. Electronic address: lei@smmu.edu.cn.

Abstract

The human epidermal growth factor receptor (EGFR) targeting chimeric monoclonal antibody, cetuximab (Erbitux®), is a widely used drug in the treatment of metastatic colorectal cancer. However, the activation of the extensive crosstalk among the EGFR family receptors as well as other tyrosine kinase receptors (RTKs) impairs the efficacy of the drug by fueling acquired resistance. To identify the responsible potential activation pathway underlying cetuximab resistance and generate novel treatment strategies, cetuximab-resistant colorectal cancer cell lines were generated and validated and a functional RNAi screen targeting human RTKs was used to identify extensive receptor tyrosine kinase signaling networks established in resistant cancer cells. MET, Axl, and IGF-1R were identified as contributors to the acquired resistance to cetuximab. Targeting vectored immunoprophylaxis (VIPs) to different RTKs were generated and characterized. Different VIP approaches were evaluated in vivo with parental and cetuximab-resistance xenografts and the RTKs in resistant cancer xenografts were inhibited with VIPs via re-sensitization to cetuximab treatment. Combination of VIPs was more broadly efficacious, mechanistically, due to co-blocking the EGFR/Axl/MET signaling pathway, which was cross-activated in the resistant cell lines. Moreover, a VIP-based procedural treatment strategy not only eliminated the tumor but also afforded long-lasting protection from tumor recurrence and resistance. Overall, EGFR-related RTK pathway-network activation represents a novel mechanism underlying cetuximab resistance. A broad VIP combination strategy and VIP-based procedural treatment strategy may be a recommended addition to cetuximab-based targeted therapy. Our results establish a new principle to achieve combined RTK inhibition and reverse drug resistance using a VIP approach.

KEYWORDS:

Acquire resistance; Broad targeted therapy; CRC; Viral vectors

PMID:
27569653
DOI:
10.1016/j.canlet.2016.08.022
[Indexed for MEDLINE]

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