A preclinical evaluation of SKLB261, a multikinase inhibitor of EGFR/Src/VEGFR2, as a therapeutic agent against pancreatic cancer.

Abstract

The clinical prognosis of pancreatic cancer remains rather disappointing despite tremendous efforts in exploring medical treatments in the past two decades. Development of more effective treatment strategies is still desperately needed to improve outcomes in patients with pancreatic cancer. SKLB261 is a multikinase inhibitor obtained recently through a lead optimization. In this investigation, we shall evaluate its anti-pancreatic cancer effects both in vitro and in vivo. SKLB261 is a multikinase inhibitor potently inhibiting EGFR, Src, and VEGFR2 kinases. It could significantly inhibit cell proliferation, migration, and invasion, and induce apoptosis in cellular assays of human pancreatic cancer cells that are sensitive or resistant to dasatinib and/or gemcitabine. Western blot analysis showed that SKLB261 inhibited the activation of EGFR and Src kinases as well as their downstream signaling proteins, including FAK, ERK, and STAT3. SKLB261 also showed potent antiangiogenic effects in transgenic zebrafish models. In vivo, SKLB261 displayed more potent antitumor activities than dasatinib, gemcitabine, or erlotinib in pancreatic cancer xenografts, including BxPC-3, PANC-1, AsPC-1, and HPAC. Furthermore, mice receiving SKLB261 therapy showed significant survival advantage compared with vehicle-treated and gemcitabine-treated groups in an experimental metastasis model of pancreatic cancer. These data, together with the good pharmacokinetic properties and low toxicity of this compound, provide a rationale for the ongoing clinical evaluation of SKLB261 in the treatment of pancreatic cancer.

• Authors: Youli Pan, Mingwu Zheng, Lei Zhong, Jiao Yang, Shu Zhou, Ya Qin, Rong Xiang, Yuzong Chen, Sheng-Yong Yang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 2 Pg. 407-18 (Feb 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25519702 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Piperazines
• Protein Kinase Inhibitors
• Recombinant Proteins
• SKLB261
• 2-Aminopurine
• ErbB Receptors
• Vascular Endothelial Growth Factor Receptor-2
• src-Family Kinases

Topics

• 2-Aminopurine (analogs & derivatives, chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• G1 Phase (drug effects)
• Humans
• Mice, Nude
• Neoplasm Metastasis (pathology)
• Pancreatic Neoplasms (drug therapy, pathology)
• Piperazines (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Rats, Sprague-Dawley
• Recombinant Proteins (metabolism)
• Resting Phase, Cell Cycle (drug effects)
• Signal Transduction (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)
• Zebrafish
• src-Family Kinases (antagonists & inhibitors, metabolism)