Multikinase Inhibitor Targeting MET Research Articles

Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via AKT/GSK-3\u03b2/NF-\u03baB signaling pathway

Cabozantinib is a multi-kinase inhibitor targeting MET, AXL, and VEGFR2, and has been approved for use in multiple malignancies. The means by which Cabozantinib acts to target colorectal cancer (CRC) cells remains poorly understood, and we sought to investigate how this drug disrupts cell growth in CRC cells and how it interacts to enhance the efficacy of other chemotherapeutic agents. In this study, we found that Cabozantinib activated a p65-dependent signaling pathway in response to both inhibition of AKT and activation of glycogen synthase kinase 3β (GSK3β), leading to upregulation of PUMA in CRC cells regardless of p53 activity. PUMA upregulation facilitates CRC apoptosis in response to Cabozantinib, which also acts synergistically with the chemotherapeutic agents Cetuximab and 5-FU to induce robust apoptosis in a PUMA-dependent manner. Eliminating PUMA expression ablated this apoptosis induced by Cabozantinib in xenograft mouse model. Our findings revealed that Cabozantinib acts to drive CRC cells apoptosis via a PUMA-dependent mechanism, thus identifying PUMA expression as a potential predictor of Cabozantinib efficacy and a potential novel therapeutic target.

MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells.

Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs. In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues. In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs. The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.

Abstract 404: MK2461 suppress progression of pancreatic cancer disrupting interaction between pancreatic cancer cells and stellate cells

Abstract Pancreatic cancer is characterized excessive desmoplasia, which occupies 80% of pancreatic cancer tissue and mainly consists of pancreatic stellate cells (PSCs). Desmoplasia has been shown to play an important role in the progression, invasion, and metastasis of pancreatic cancer and has been implicated in the development of resistance to chemotherapy and radiotherapy. Growth factors are one of the components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. Therefore, blocking growth factor signaling could suppress cancer progression. In this study, we profiled the expression of receptor tyrosine kinases (RTKs) with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry (LC-MS/MS) in PCCs and PSCs. In PCCs, epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) levels were elevated compared with those in PSCs. In PSCs, platelet-derived growth factor receptor beta (PDGFRβ) and MET were upregulated compared with other RTKs. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. In addition, MK2461, a multikinase inhibitor targeting MET and PDGFRβ, suppressed the effects of conditioned medium on PCCs and PSCs. In addition, MK2461 significantly inhibited tumor growth in mice xenograft model. In conclusion, PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs. Moreover, MK2461 may have therapeutic potential in the treatment of pancreatic cancer by targeting the interaction between PCCs and PSCs. Citation Format: Koetsu Inoue, Hideo Ohtsuka, Fuyuhiko Motoi, Daisuke Douchi, Shuhei Kawasaki, Kei Kawaguchi, Kunihiro Masuda, Koji Fukase, Shinobu Ohnuma, Takeshi Naitoh, Yu Katayose, Shinichi Egawa, Michiaki Unno. MK2461 suppress progression of pancreatic cancer disrupting interaction between pancreatic cancer cells and stellate cells. [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 404. doi:10.1158/1538-7445.AM2015-404

Abstract SY23-03: Oncogenic signal transduction via the hepatocyte growth factor/Met receptor kinase pathway

Abstract SY23-03: Oncogenic signal transduction via the hepatocyte growth factor/Met receptor kinase pathway