Franziska Siegel

Acetyl-CoA carboxylase inhibitors attenuate WNT and Hedgehog signaling and suppress pancreatic tumor growth

Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in de novo fatty acid synthesis, and its ACC1 isoform is overexpressed in pancreatic and various other cancers. The activity of many oncogenic signaling molecules, including WNT and Hedgehog (HH), is post-translationally modified by lipidation. Here, we report that inhibition of ACC by a small molecule inhibitor, BAY ACC002, blocked WNT3A lipidation, secretion, and signaling. In pancreatic cancer cells, where WNT and HH are key oncogenic drivers, ACC inhibition simultaneously suppressed WNT and HH signaling, and led to anti-proliferative effects. Treatment with ACC inhibitors blocked tumor growth and converted the poorly differentiated histological phenotype to epithelial phenotype in multiple cell line-based and patient-derived pancreatic cancer xenograft models. Together, our data highlight the potential utility of ACC inhibitors for pancreatic cancer treatment, and provide novel insight into the link between upregulated de novo fatty acid synthesis in cancer cells, protein lipidation, and oncogenic signaling.

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 Siegel, Antje M. Wengner, Claudia Lange, Ulf Boemer, Knut Eis, Florian Puehler, Martin Michels, Franz von Nussbaum, Karl Ziegelbauer, Dominik Mumberg, Kirstin Petersen. Preclinical mode of action and anti-tumor efficacy of the selective MKNK1 inhibitor BAY 1143269 in NSCLC models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 341.

Abstract 2604: Preclinical anti-tumor efficacy and mode of action of a novel, orally available, selective MKNK1 inhibitor [BAY 1143269]

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 was shown to regulate mRNA translation by phosphorylating the translation initiation factor eIF4E (eukaryotic translation initiation factor 4E), known to be critical for malignant transformation but dispensable for translation in normal cells. In addition, MKNK is involved in resistance mechanisms to cancer therapeutics. Thus, the inhibition of MKNK1 activity may provide an innovative approach for anti-cancer therapy. BAY 1143269 was identified as a potent and selective inhibitor of MKNK1 activity with an unprecedented mode of action. It inhibits the phosphorylation of eIF4E in various cancer cell lines in vitro and leads to reduced expression of MKNK-regulated translational downstream targets, including survivin, Cdc25C and cyclin B1. In addition, BAY 1143269 potently inhibits cytokine release in LPS stimulated human blood. In vivo, BAY 1143269 shows a significant monotherapy efficacy in non-small cell lung cancer (NSCLC), colorectal cancer and melanoma xenograft models after an once daily, oral application of 200 mg/kg in mice and 70 mg/kg in rats. Furthermore, combination treatment with chemotherapy and BAY 1143269 gives additive efficacy in several NSCLC cell lines and patient-derived xenograft models leading to partial response (Lu7558, A549), stable disease (Lu7187, Lu7166) or significant delay in tumor re-growth versus chemotherapy alone after stop of treatment (Lu7558). In summary, BAY 1143269 is a selective, orally available MKNK1 inhibitor that demonstrates preclinical in vivo efficacy in mono- and combination therapy and may provide therapeutic benefit for patients with solid tumors. Citation Format: Susann Santag, Franziska Siegel, Antje Margret Wegner, Claudia Schneider, Ulf Boemer, Knut Eis, Florian Puehler, Martin Michels, Franz von Nussbaum, Karl Ziegelbauer, Dominik Mumberg, Kirstin Petersen. Preclinical anti-tumor efficacy and mode of action of a novel, orally available, selective MKNK1 inhibitor [BAY 1143269]. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2015-2604