pd-0325901 and Urinary-Bladder-Neoplasms

Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.

Topics: Animals; Benzamides; Cell Line, Tumor; Diphenylamine; Disease Progression; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Kaplan-Meier Estimate; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins c-met; Pyrazoles; Quinolines; Receptors, Transforming Growth Factor beta; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays

Metastatic bladder cancer is a serious condition with a 5-year survival rate of approximately 14 %, a rate that has remained unchanged for almost three decades. Thus, there is a profound need to identify the driving mutations for these aggressive tumors to better determine appropriate treatments. Mutational analyses of clinical samples suggest that mutations in either the phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) or RAS/MEK/ERK pathways drive bladder cancer progression, although it remains to be tested whether the inhibition of either (or both) of these pathways can arrest PI3K/mTOR- or Ras-driven proliferation.. Herein, we used several bladder cancer cell lines to determine drug sensitivity according to genetic background and also studied mouse models of engrafted UM-UC-3 cells and patient-derived xenografts (PDXs) to test PI3K/mTOR and MEK inhibition in vivo.. Inhibition of these pathways utilizing PF-04691502, a PI3K and mTOR inhibitor, and PD-0325901, a MEK inhibitor, slowed the tumor growth of PDX models of bladder cancer. The growth inhibitory effect of combination therapy was similar to that of the clinical maximum dose of cisplatin; mechanistically, this appeared to predominantly occur via drug-induced cytostatic growth inhibition as well as diminished vascular endothelial growth factor secretion in the tumor models. Kinase arrays of tumors harvested after treatment demonstrated activated p53 and Axl as well as STAT1 and STAT3.. Taken together, these results indicate that clinically relevant doses of PF-04691502 and PD-0325901 can suppress bladder tumor growth in PDX models, thus offering additional potential treatment options by a precision medicine approach.

Topics: Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Diphenylamine; Disease Models, Animal; Female; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Random Allocation; TOR Serine-Threonine Kinases; Urinary Bladder Neoplasms; Xenograft Model Antitumor Assays