Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition.
The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers.
Division of Monoclonal Antibodies; Office of Biotechnology Products; Office of Pharmaceutical Science; Center for Drug Evaluation and Research; US Food and Drug Administration; Bethesda, MD USA.
Milos
M
Dokmanovic
Department of Pathology; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
Yun
Y
Wu
Division of Monoclonal Antibodies; Office of Biotechnology Products; Office of Pharmaceutical Science; Center for Drug Evaluation and Research; US Food and Drug Administration; Bethesda, MD USA.
Yi
Y
Shen
Department of Pathology; University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
Jieqing
J
Chen
Division of Monoclonal Antibodies; Office of Biotechnology Products; Office of Pharmaceutical Science; Center for Drug Evaluation and Research; US Food and Drug Administration; Bethesda, MD USA.
Dianne S
DS
Hirsch
Division of Monoclonal Antibodies; Office of Biotechnology Products; Office of Pharmaceutical Science; Center for Drug Evaluation and Research; US Food and Drug Administration; Bethesda, MD USA.
Wen Jin
WJ
Wu
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D000077341:Lapatinib; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077341:Lapatinib; D051058:Oncogene Protein v-akt; D047428:Protein Kinase Inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src); D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C085377:MATK protein, human
CHK/MATK; ErbB2-Y1248; ErbB2/HER2; breast cancer; trastuzumab