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Combating acquired resistance to trastuzumab by an anti-ErbB2 fully human antibody

Chao Wang1, Lingfei Wang1, Xiaojie Yu1

  • 1International Joint Cancer Institute and Department of Pharmaceutical Sciences, The Second Military Medical University, Shanghai, People's Republic of China.

Oncotarget
|May 18, 2017
PubMed

Insights

A novel antibody, H2-18, shows significant antitumor activity against ErbB2-amplified cancers that are resistant to trastuzumab. This antibody effectively overcomes acquired resistance, offering a potential new treatment strategy.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Trastuzumab resistance is a major challenge in treating ErbB2-amplified cancers, with high rates of both de novo and acquired resistance.
  • Existing resistance mechanisms differ, with acquired resistance often involving alterations dependent on ErbB2 activity.

Purpose of the Study:

  • To investigate the efficacy of H2-18, an ErbB2 domain I-specific antibody, in overcoming acquired trastuzumab resistance.
  • To evaluate H2-18's antitumor activity in a preclinical model of acquired trastuzumab resistance.

Main Methods:

  • Developed a trastuzumab-resistant gastric cancer cell line (NCI-N87-TraRT) by continuous trastuzumab treatment.
  • Assessed the antitumor efficacy of H2-18 compared to pertuzumab and trastuzumab in NCI-N87-TraRT tumor-bearing mice.

Main Results:

  • H2-18 demonstrated significantly greater antitumor activity than pertuzumab and trastuzumab in the NCI-N87-TraRT model.
  • H2-18's efficacy in overcoming acquired resistance may be linked to its potent programmed cell death-inducing activity via the RIP1-ROS-JNK-c-Jun pathway.

Conclusions:

  • H2-18 shows potential in circumventing acquired trastuzumab resistance in ErbB2-overexpressing cancers.
  • H2-18 represents a promising therapeutic candidate for patients who develop resistance to current ErbB2-targeted therapies.
Keywords:
ErbB2acquired resistance to trastuzumabdomain I- specific antibodygastric cancerprogrammed cell death

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