Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells.
ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin downregulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNFalpha, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNFalpha-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.
Shell
Scott A
SA
Targeted Molecular Diagnostics, Westmont, Illinois 60559, USA.
Lyass
Ljuba
L
Trusk
Patricia B
PB
Pry
Karen J
KJ
Wappel
Robert L
RL
Bacus
Sarah S
SS
D055372:AMP-Activated Protein Kinases; D000911:Antibodies, Monoclonal / Q000633:toxicity; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D016158:Genes, p53; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000633:toxicity*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D000068878:Trastuzumab
D055372:AMP-Activated Protein Kinases; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C506645:GW2974