1. Academic Validation
  2. Dual Inhibition of PIK3C3 and FGFR as a New Therapeutic Approach to Treat Bladder Cancer

Dual Inhibition of PIK3C3 and FGFR as a New Therapeutic Approach to Treat Bladder Cancer

  • Clin Cancer Res. 2018 Mar 1;24(5):1176-1189. doi: 10.1158/1078-0432.CCR-17-2066.
Chun-Han Chen 1 Chun A Changou 2 3 4 Tsung-Han Hsieh 5 Yu-Ching Lee 6 Cheng-Ying Chu 6 Kai-Cheng Hsu 2 Hao-Ching Wang 3 Yu-Chen Lin 1 Yan-Ni Lo 6 Yun-Ru Liu 5 Jing-Ping Liou 7 Yun Yen 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 3 Graduate Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
  • 6 Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 8 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. yyen@tmu.edu.tw.
Abstract

Purpose: MPT0L145 has been developed as a FGFR Inhibitor exhibiting significant anti-bladder Cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms.Experimental Design: Autophagy flux, morphology, and intracellular organelles were evaluated by Western blotting, transmission electron microscope, and fluorescence microscope. Molecular docking and surface plasmon resonance assay were performed to identify drug-protein interaction. Lentiviral delivery of cDNA or shRNA and CRISPR/Cas9-mediated genome editing was used to modulate gene expression. Mitochondrial oxygen consumption rate was measured by a Seahorse XFe24 extracellular flux analyzer, and ROS level was measured by flow cytometry.Results: MPT0L145 persistently increased incomplete Autophagy and phase-lucent vacuoles at the perinuclear region, which were identified as enlarged and alkalinized late-endosomes. Screening of a panel of lipid kinases revealed that MPT0L145 strongly inhibits PIK3C3 with a Kd value of 0.53 nmol/L. Ectopic expression of PIK3C3 reversed MPT0L145-increased cell death and incomplete Autophagy. Four residues (Y670, F684, I760, D761) at the ATP-binding site of PIK3C3 are important for the binding of MPT0L145. In addition, MPT0L145 promotes mitochondrial dysfunction, ROS production, and DNA damage, which may in part, contribute to cell death. ATG5-knockout rescued MPT0L145-induced cell death, suggesting simultaneous induction of Autophagy is crucial to its Anticancer activity. Finally, our data demonstrated that MPT0L145 is able to overcome cisplatin resistance in bladder Cancer cells.Conclusions: MPT0L145 is a first-in-class PIK3C3/FGFR Inhibitor, providing an innovative strategy to design new compounds that increase Autophagy, but simultaneously perturb its process to promote bladder Cancer cell death. Clin Cancer Res; 24(5); 1176-89. ©2017 AACR.

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Products
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  • HY-12768
    99.80%, CSF-1R Inhibitor