Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression.
Darshan S ChandrashekarBalabhadrapatruni V S K ChakravarthiAlyncia D RobinsonJoshua C AndersonSumit AgarwalSai Akshaya Hodigere BalasubramanyaMarie-Lisa EichAkhilesh Kumar BajpaiSravanthi DavuluriMaya S GuruArjun S GuruGurudatta NaikDeborah L Della MannaKshitish K AcharyaShannon CarskadonUpender ManneDavid K CrossmanJames E FergusonWilliam E GrizzleNallasivam PalanisamyChristopher D WilleyMichael R CrowleyGeorge J NettoEddy S YangSooryanarayana VaramballyGuru SonpavdePublished in: Oncogene (2020)
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.
Keyphrases
- tyrosine kinase
- single cell
- spinal cord injury
- type diabetes
- small cell lung cancer
- induced apoptosis
- epidermal growth factor receptor
- end stage renal disease
- squamous cell carcinoma
- poor prognosis
- chronic kidney disease
- cell proliferation
- emergency department
- stem cells
- oxidative stress
- skeletal muscle
- single molecule
- mesenchymal stem cells
- rna seq
- protein kinase
- bone marrow
- cardiovascular disease
- coronary artery disease
- ejection fraction
- cell death
- high grade
- prognostic factors
- risk factors
- electronic health record
- adverse drug
- rectal cancer
- case control
- pi k akt
- cell migration