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Updated: Dec 25, 2025
3-D Cell Culture System for Studying Invasion and Evaluating Therapeutics in Bladder Cancer
Published on: September 13, 2018
Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression
Darshan S Chandrashekar1, Balabhadrapatruni V S K Chakravarthi1, Alyncia D Robinson1
1Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.
Insights
Targeting P21 (RAC1) activated kinase 4 (PAK4) shows promise for aggressive bladder cancers. Inhibiting PAK4 and protein tyrosine kinase 6 (PTK6) may overcome treatment resistance in muscle-invasive bladder carcinomas (MIBCs).
Area of Science:
- Oncology
- Molecular Biology
- Genitourinary Malignancies
Background:
- Muscle-invasive bladder carcinomas (MIBCs) are aggressive and often fatal genitourinary cancers.
- Metastatic urothelial carcinoma of the bladder typically shows resistance to chemotherapy, leading to poor prognoses.
- Tumor heterogeneity in MIBCs suggests varying sensitivities to existing therapies.
Purpose of the Study:
- To identify novel therapeutic targets in bladder cancer through multi-omic kinome profiling.
- To investigate the role of P21 (RAC1) activated kinase 4 (PAK4) in bladder cancer progression and its therapeutic potential.
- To explore combination therapies involving PAK4 inhibition for enhanced efficacy.
Main Methods:
- Multi-omic profiling of the kinome in bladder cancer patient samples.
- In vitro studies using bladder cancer cells to assess PAK4's role in proliferation and invasion.
- Pharmacological inhibition of PAK4 and evaluation of its effect on cancer cell growth.
- Transcriptomic analysis to identify molecular changes following PAK4 inhibition.
- Combination treatment with kinase inhibitors (vandetanib and dasatinib).
Main Results:
- Amplification, overexpression, and elevated kinase activity of PAK4 were identified in a subset of bladder cancer (BLCA) patients.
- PAK4 inhibition effectively reduced BLCA cell proliferation and invasion.
- Transcriptomic analysis revealed elevated protein tyrosine kinase 6 (PTK6) expression upon PAK4 inhibition.
- Combined inhibition of PAK4 and PTK6, or treatment with vandetanib and dasatinib, demonstrated enhanced anti-cancer effects.
Conclusions:
- PAK4 represents a therapeutically actionable target for a subset of MIBC patients with PAK4 amplification or overexpression.
- Combined inhibition of PAK4 and PTK6 may be a strategy to overcome resistance to PAK4-targeted therapies.
- These findings support further clinical investigation of PAK4-targeted therapies in selected BLCA patients.
