Abstract 341: Preclinical mode of action and anti-tumor efficacy of the selective MKNK1 inhibitor BAY 1143269 in NSCLC models

MKNK1 (MAP kinase-interacting serine/threonine-protein kinase, also known as Mnk1) is activated by the mitogen-activated protein kinases ERK1/2 and p38. Thus, MKNK1 signaling is involved in the cellular response to environmental stress factors and cytokines. Of particular interest, MKNK1 kinase regulates mRNA translation by phosphorylating the translation initiation factor eIF4E (eukaryotic translation initiation factor 4E), known to be critical for malignant transformation but shown to be dispensable for translation in normal cells. Phosphorylated eIF4E levels were found to be elevated in several cancer tissues, including lung cancer. MKNK1 is also involved in resistance mechanisms to cancer therapeutics. Thus, the inhibition of MKNK1 activity may provide an innovative approach for anti-cancer therapy, and in particular for lung cancer, the main cancer-related cause of death worldwide. BAY 1143269 is a potent and selective MKNK1 inhibitor and inhibits eIF4E phosphorylation and reduces MKNK1-regulated translational downstream targets in non-small cell lung cancer (NSCLC) cell lines. In this study, BAY 1143269-mediated effects on molecular mechanisms in lung cancer models were analyzed. Epithelial-mesenchymal transition (EMT) is associated with the pathogenesis of numerous lung diseases including cancer progression, metastasis and resistance. BAY 1143269 reduced expression of EMT key regulators like Snail1 and cellular junction components, as well as reduced TGFβ1-induced EMT. Accumulating evidence suggests a role for proinflammatory cytokines in the development and progression of cancer; increased serum concentrations of cytokines like interleukin 6 (IL-6) are associated with diminished lung cancer survival rates. BAY 1143269 reduced the secretion of several proinflammatory cytokines, including TNFα and IL-6 in whole blood, and affected IFN-stimulated gene expression in cell lines. Consistent with the observed effects in vitro, BAY 1143269 showed significant anti-tumor effects in vivo in cell line as well as patient derived NSCLC xenograft models in monotherapy. In combination with chemotherapeutics approved for treatment of NSCLC, BAY 1143269 improved anti-tumor effects in comparison to chemotherapy alone. In conclusion, BAY 1143269 has the potential to provide therapeutic benefit in NSCLC. A phase I study of BAY 1143269 in combination with docetaxel for subjects with advance solid tumors is ongoing (NCT02439346). Citation Format: Susann Santag, Franziska