Linifanib (ABT-869) Potentiates the Efficacy of Chemotherapeutic Agents through the Suppression of Receptor Tyrosine Kinase-Mediated AKT/mTOR Signaling Pathways in Gastric Cancer

Abstract

Gastric cancer, highly dependent on tumor angiogenesis, causes uncontrolled lethality, in part due to chemoresistance. Here, we demonstrate that linifanib (ABT-869), a novel multi-targeted receptor tyrosine kinase inhibitor, markedly augments cytotoxicity of chemotherapies in human gastric cancer. ABT-869 and chemotherapeutic agents exhibited a strong synergy to inhibit the viability of several gastric cancer cell lines, with combination index values ranging from 0.017 to 0.589. Additionally, the combination of ABT-869 and chemotherapeutic agents led to remarkable suppression of vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo. Importantly, in a preclinical gastric cancer xenograft mouse model, drug co-treatments led to increased mouse survival as well as a synergistic reduction in tumor size and the inhibition of tumor angiogenesis. Mechanistic studies further revealed that all of the co-treatments containing ABT-869 resulted in decreased activation of the VEGF receptor, the epidermal growth factor receptor and the insulin growth factor receptor. Inhibition of these receptor tyrosine kinases consequently attenuated the activation of the downstream AKT/mTOR signaling pathway both in cultured gastric cancer cells and in gastric cancer xenografts. Collectively, our findings suggest that the addition of ABT-869 to traditional chemotherapies may be a promising strategy for the treatment of human gastric cancer.

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

“…Linifanib is a potent ATP‐competitive inhibitor for VEGFR‐2, Flt‐1/3, and PDGFRβ. Functionally similar to sorafenib, linifanib is an orally available multitarget RTKI with potent antiangiogenic effects . Regorafenib is an oral multitarget inhibitor of VEGFR‐2, Tie‐2, PDGFR, and FGFR .…”

“…Functionally similar to sorafenib, linifanib is an orally available multitarget RTKI with potent antiangiogenic effects. 157 Regorafenib is an oral multitarget inhibitor of VEGFR-2, Tie-2, PDGFR, and FGFR. 158 Cabozantinib (Cometriq, Exelixis) was granted orphan drug status for the treatment of medullary thyroid cancer in 2012.…”

High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice

“…These compounds induced a pattern of gene expression in multiple cell lines that mimicked the striatal gene expression pattern found in high-runners relative to controls as indicated by the high positive CSs. Further, these compounds are known to affect monoamine signaling and have some literature on toxicology and efficacy in animal and human studies (Chen et al 2016;Sofuoglu et al 1993;Zhang et al 2007).…”

“…Considering CSs generated from all the cell lines in the database, we found that the receptor tyrosine kinase (RTK) inhibitor, Linifanib (Chen et al 2016), also displayed a high positive CS. The RTKs are high-affinity cell surface receptors for peptide growth factors, cytokines and hormones.…”

Association of Vascular Endothelial Growth Factor (VEGF) Gene Polymorphisms With Gastric Cancer and Its Development, Prognosis, and Survival

“…Gastric cancer is one of the most common diagnosed cancers and cause of cancer-related deaths worldwide. 1 – 3 It is a heterogeneous disease with diverse histological and molecular subtypes. 2 Although there have been vital improvements in diagnostic and therapeutic techniques for gastric cancer, prognosis for patients remains poor.…”