Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression

Abstract

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Disease incidence and survival rates vary based on aggressiveness and treatment options. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. For a minority (~20%) of patients, T-cell checkpoint inhibitors provide durable benefits following prior platinum therapy. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting heterogeneity in these tumors and pointing to the importance of molecular characterization of MIBCs to provide effective treatment. We have performed multi-omic profiling of the kinome to identify therapeutic targets that are overexpressed in a subset of BLCAs. Our analyses revealed amplification and overexpression of P21 (RAC1) activated kinase 4 (PAK4) in a subset of BLCAs. For these tumors, multiplex kinase assay profiling identified corresponding PAK4 target substrates. By performing experiments using cultured bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, our studies showed 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.Similarly, RNA interference of PAK4 led to elevated expression of PTK6. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared to 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.

[Retracted] Interfering with pak4 Protein Expression Affects Osteosarcoma Cell Proliferation and Migration

“…It can inhibit apoptosis of tumor cells, promote cell survival, cause uncontrolled growth, trigger cell morphology to lose its regulatory function, inhibit cell adhesion, and promote cell migration and tumor formation. In addition, it is capable of regulating the independent growth of the cells by relying on independent kinase activity to stimulate the growth, invasion, and metastasis of tumor cells [9]. These outcomes discovered that PAK4 may serve a critical part in the occurrence and progression of osteosarcoma tumors.…”

Prognostic value and potential biological functions of ferroptosis‑related gene signature in bladder cancer

“…ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE76211) and GSE130598 (https://www.ncbi.nlm.nih.gov/geo/query/acc. cgi?acc=GSE130598) were used to evaluate the mRNA level of G6PD in BC and adjacent normal tissue (18,19).…”

ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors

“…As previously described (46), after IRB approval at the University of Alabama-Birmingham (#X120917005), written informed consent from patients, and after pathologic stage and grade determination, protein lysates were prepared from human bladder cancer samples and surrounding normal mucosa, using tissues from radical cystectomies.…”