The covalent JNK inhibitor, JNK-in-8, synergizes with lapatinib to cause cell death in basal-like breast cancer cell lines
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Basal-like and Claudin-low breast cancers have the worst prognosis and represent 15-20% of breast cancers diagnosed each year. Endocrine and molecularly targeted therapies are ineffective for these tumors due to lack of Estrogen Receptor (ER) or Human Epidermal Growth Factor Receptor 2 (HER2) overexpression, leaving chemotherapy as the only option for treatment. New molecularly targeted therapies for this subtype are urgently needed. High expression of c-Jun N-terminal Kinase 2 (JNK2) in human basal-like breast cancers significantly correlates with decreased disease-free survival. In mouse models, JNK2 promotes basal-like tumor progression, increases Epidermal Growth Factor Receptor (EGFR)-mediated migration, upregulates Epithelial and Mesenchymal (EMT) gene expression, and promotes metastasis. Hypothesis: Due to the central role of JNK in Basal-like tumor progression, JNK inhibition may be therapeutic in Basal-like breast cancer, especially when combined with the EGFR/HER2 inhibitor lapatinib (Tykerb™). Treatment with the covalent JNK inhibitor, JNK-IN-8, synergizes with lapatinib to cause cell death, while these drugs as single agents have little effect on cell viability. Our studies suggest that JNK1 and HER2 are the key targets in this response. vi Intracellular response to lapatinib and JNK-IN-8 combination treatment significantly reduces DNA binding activity of Nuclear Factor kappa B (NFκB), and induces a 10-fold increase in Reactive Oxygen Species (ROS) accumulation that is cytotoxic. We hypothesize that inhibition of NFκB signaling by JNK-IN-8 and lapatinib causes ROS accumulation that triggers apoptosis. However, the combination of JNK-IN-8 and lapatinib leads to a higher degree of cell killing than pharmacologic inhibition of canonical NFκB signaling alone. Mechanisms involving JNK-IN-8 and lapatinib regulation of non-canonical NFκB members will be explored in the future. An additional mechanism of synergy could involve inhibition of AP-1 transcriptional activity which may exacerbate NFκB transcriptional inhibition through cooperation of these transcription factors at various promoters. JNK-IN-8 formulation for in vivo studies will enable us to determine whether JNK-IN-8 and lapatinib synergize in mouse models of Basal-like breast cancer. Success here will legitimize human studies with this combination to establish whether there will be a therapeutic benefit for patients with Basal-like breast cancers whose lack of molecularly targeted therapies represents an unmet medical need.