RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

Nat Commun. 2021 Nov 5;12(1):6427. doi: 10.1038/s41467-021-26018-z.

Abstract

HER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody-drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ado-Trastuzumab Emtansine / therapeutic use*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Female
  • Humans
  • Trastuzumab / therapeutic use*
  • rab5 GTP-Binding Proteins / genetics
  • rab5 GTP-Binding Proteins / metabolism*

Substances

  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • rab5 GTP-Binding Proteins
  • pertuzumab
  • Trastuzumab
  • Ado-Trastuzumab Emtansine

Associated data

  • ClinicalTrials.gov/NCT01042379
  • ClinicalTrials.gov/NCT01702571