Successful targeting of ErbB2 receptors-is PTEN the key?
Women with ErbB2-positive breast cancer have a poor prognosis, and frequently, chemotherapy treatment is ineffective. The ErbB2-targeted antibody trastuzumab improves survival when given with chemotherapy to patients with ErbB2-overexpressing metastatic disease, but treatment is not curative, and primary resistance is common. Postulated mechanisms of action for trastuzumab include immune-mediated cytotoxicity and receptor downmodulation. A study in this issue of Cancer Cell suggests that trastuzumab causes rapid activation of the PTEN lipid phosphatase, which in turn downregulates the phosphatidylinositol 3'-kinase (PI3K) pathway. Resistance to trastuzumab occurs when PTEN function is lost, suggesting that PTEN activation is a critical component of the therapeutic effect.
Department of Medicine, Division of Oncology, Washington University School of Medicine and Siteman Cancer Center, Campus Box 8056, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Robert J
RJ
Crowder
Donald P
DP
Lombardi
Matthew J
MJ
Ellis
D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D025521:Tumor Suppressor Proteins; C494929:PTEN protein, human