pki-166 and Breast-Neoplasms

Several agents that target one or more members of the erbB family of receptor tyrosine kinases are currently undergoing clinical investigation. The monoclonal antibody trastuzumab has been shown effective in erbB2-expressing metastatic breast cancer when administered as a single agent or in combination with cytotoxic chemotherapy. Toxicities associated with trastuzumab include infusion-related fever and chills, hypersensitivity reactions, and congestive heart failure. C225 is a monoclonal antibody directed against the epidermal growth factor receptor, which has shown encouraging antitumor activity in early clinical development. The orally active tyrosine kinase inhibitors show encouraging antitumor activity in preclinical models and early clinical trials. Members of this class currently in clinical development include ZD1839, OSI-774, and CI-1033. Evidence to date suggests that the major role for erbB receptor-targeting drugs will be in combined therapy to enhance response to cytotoxic drugs, and in long-term monotherapy to maintain response and prevent disease progression or recurrence.

Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Cetuximab; Enzyme Inhibitors; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Protein-Tyrosine Kinases; Pyrimidines; Pyrroles; Quinazolines; Receptor, ErbB-2; Trastuzumab

The ErbB1 and ErbB2 receptor tyrosine kinases (RTKs) play important roles in the development of numerous types of human cancer and, as such, have been pursued as anticancer targets. To understand the mechanisms contributing to the response of tumor cells to receptor-directed therapeutics, the sensitivity of the ErbB receptor-overexpressing tumor cell lines BT474 and MKN7 to specific inhibitors has been examined. The inhibitors used included monoclonal antibody (mAb) 4D5, which targets ErbB2, and the small molecular weight kinase inhibitors CGP59326 and PKI166, which block the activity of ErbB1 or both ErbB1 and ErbB2, respectively. We had reported previously that although both BT474 and MKN7 cells overexpress ErbB2, only BT474 cells show an antiproliferative response to mAb 4D5 treatment. Here, we show that MKN7 cells, which also overexpress ErbB1, are sensitive to CGP59326, displaying a 60% decrease in their proliferation after treatment with this inhibitor. Most carcinomas express multiple ErbB receptors as well as EGF-related ligands, a situation favoring activation of numerous combinations of ligand-activated receptors. Considering this, the sensitivity of MKN7 and BT474 cells to CGP59326 and mAb 4D5, respectively, was also tested in the presence of exogenous ligands. Treatment of MKN7 cells with CGP59326 in the presence of heregulin (HRG), which activates ErbB2/ErbB3, attenuated the antiproliferative effect of CGP59326 by 50%; MKN7 cells engineered to overexpress ErbB3 were completely rescued from CGP59326 by HRG. Likewise, BT474 cells treated with mAb 4D5 in the presence of epidermal growth factor, betacellulin, and HRG were rescued from its antiproliferative effects by 57, 84, and 90%, respectively. In both MKN7 and BT474 tumor cells, the degree of ligand-induced rescue from the inhibitors correlated with the potency of ErbB receptor activation and stimulation of the PI3K and MAPK intracellular signaling pathways. In comparison with the monospecific agents, treatment with the bispecific ErbB1/ErbB2 kinase inhibitor PKI166 almost completely prevented the EGF-related ligand-induced bypass of the proliferation block in the MKN7 and BT474 cells. These data suggest that the efficacy of anticancer drugs that block a single ErbB receptor may be compromised by the presence of exogenous epidermal growth factor-related ligands, a phenomenon that could be averted by simultaneously blocking multiple ErbB receptors.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Betacellulin; Breast Neoplasms; Cell Division; Drug Interactions; Enzyme Inhibitors; Epidermal Growth Factor; ErbB Receptors; G1 Phase; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Neuregulin-1; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Receptor, ErbB-2; Signal Transduction; Stomach Neoplasms; Substrate Specificity; Tumor Cells, Cultured