Abstract
BackgroundLapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. In this study, we examined mechanisms associated with enhancing the activity of lapatinib via combination with other therapies.MethodsIn the present studies, estrogen receptor (ER) positive and ER negative breast cancer cells were genetically manipulated to up- or downregulate eIF2-alpha, its phospho-mutant, Nck1, or Nck2, then treated with OSU-03012, lapatinib or the combination and assayed for cytotoxicity/cytostaticity using clonogenic assays.ResultsTreatment of breast cancer cell lines with lapatinib and OSU-03012 (a small molecule derivative of the Cox-2 inhibitor celecoxib) induced synergistic cytotoxic/cytostatic effects. This combination therapy corresponded to an increase in the phosphorylation of eIF2-α at serine51 and a decrease in Nck1 expression. Ectopic expression of phospho-mutant eIF2-α (Ser51Ala) or downregulation of eIF2-α in addition to downregulation of the eIF2-α kinase PERK inhibited the synergistic and cytotoxic effects. Furthermore, ectopic expression of Nck1, but not Nck2 abolished the decrease in cell viability observed in combination-treated cells. Downregulation of Nck1 failed to “rescue” the ablation of the cytotoxic/cytostatic effects by the phospho-mutant of eIF2-α (Ser51Ala) demonstrating that Nck1 downregulation is upstream of eIF2-α phosphorylation in the anti-survival pathway activated by lapatinib and OSU-03012 treatment. Finally, co-immunoprecipitation assays indicated that eIF2-α dissociates from the Nck1/PP1 complex after OSU-03012 and lapatinib co-treatment.ConclusionsThese data indicate that OSU-03012 and lapatinib co-treatment is an effective combination therapy, which functions to enhance cell killing through the Nck1/eIF2 complex. Hence, this complex is a novel target for the treatment of metastatic breast cancer.
Highlights
Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer
Combination therapies are especially useful in the treatment of many cancers, in part due to the ability of separate drugs to target multiple separate survival pathways upregulated in many cancer lineages [40]
We showed that OSU-03012 and lapatinib synergized to induce cell death in both an estrogen receptor (ER) positive and an ER negative breast cancer cell line suggesting that this therapeutic model may be effective against a variety of breast cancer phenotypes
Summary
Lapatinib is characterized as an ErbB1/ErbB2 dual inhibitor and has recently been approved for the treatment of metastatic breast cancer. Metastasis is the main cause of breast cancer related deaths, and these metastases are only poorly controlled with first. Phosphorylation leads downstream to the activation of various signaling cascades such as the extracellular-regulated kinase (ERK), and the Akt kinase cascades. These cascades lead to propagation of both survival and death signals [7,8]. Lapatinib (Tykerb, GSK), an ErbB1/2 inhibitor, was approved for the treatment of metastatic breast cancer, as lapatinib is implicated in better outcomes in patients with metastases. Therapies which enhance lapatinib-induced cell killing are needed in the clinic
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