Insulin-like growth factor-1 receptor and ErbB kinase inhibitor combinations block proliferation and induce apoptosis through cyclin D1 reduction and Bax activation.
The insulin-like growth factor-1 receptor (IGF-1R) and ErbB family of receptors are receptor tyrosine kinases that play important roles in cancer. Lack of response and resistance to therapies targeting ErbB receptors occur and are often associated with activation of the IGF-1R pathway. Combinations of agents that inhibit IGF-1R and ErbB receptors have been shown to synergistically block cancer cell proliferation and xenograft tumor growth. To determine the mechanism by which targeting both IGF-1R and ErbB receptors causes synergistic effects on cell growth and survival, we investigated the effects of combinations of selective IGF-1R and ErbB kinase inhibitors on proliferative and apoptotic signaling. We identified A431 squamous cell carcinoma cells as most sensitive to combinations of ErbB and IGF-1R inhibitors. The inhibitor combinations resulted in not only blockade of A431 cell proliferation, but also induced apoptosis, which was not seen with either agent alone. Upon examining phosphorylation states and expression levels of proteins in the IGF-1R and ErbB signaling pathways, we found a correlation between the ability of combinations to inhibit proliferation and to decrease levels of phosphorylated Akt and cyclin D1. In addition, the massive cell death induced by combined IGF-1R/ErbB inhibition was associated with Mcl-1 reduction and Bax activation. Thus, targeting both IGF-1R and ErbB receptors simultaneously results in cell cycle arrest and apoptosis through combined effects on Akt, cyclin D1, and Bax activation.
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Julie L
JL
Wilsbacher
Qian
Q
Zhang
Lora A
LA
Tucker
Robert D
RD
Hubbard
George S
GS
Sheppard
Nwe Y
NY
Bamaung
Steve D
SD
Fidanze
Gary T
GT
Wang
Xiaoming
X
Hu
Steven K
SK
Davidsen
Randy L
RL
Bell
Jieyi
J
Wang
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; D056741:Cyclin D; D016213:Cyclins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D018739:Oncogene Proteins v-erbB; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt