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.

中文翻译：

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具有治疗作用的PAK4被扩增，过度表达并参与膀胱癌的进展。

肌肉浸润性膀胱癌（MIBC）是侵袭性泌尿生殖系统恶性肿瘤。膀胱转移性尿路上皮癌通常可通过当前的化学疗法治愈，并导致早期死亡。最近的研究已经确定了对一线治疗有不同敏感性的MIBC分子亚型，提示肿瘤异质性。我们已经对膀胱癌患者的肌组进行了多组学分析，目的是确定治疗靶点。我们的分析显示，在部分膀胱癌（BLCA）中，P21（RAC1）激活的激酶4（PAK4）的扩增，过表达和激酶活性升高。使用膀胱癌细胞，我们证实了PAK4在BLCA细胞增殖和侵袭中的作用。此外，我们观察到PAK4抑制剂可有效减少BLCA细胞的生长。转录组学分析发现，在用PAK4抑制剂治疗和PAK4的RNA干扰后，另一种激酶（蛋白酪氨酸激酶6（PTK6））的表达升高。与单独使用任一药物相比，激酶抑制剂（vandetanib和dasatinib）的联合治疗均显示出更高的敏感性。因此，PAK4对于在其肿瘤中具有扩增和/或过表达的PAK4的一部分MIBC患者可能具有治疗作用。我们的结果还表明，联合抑制PAK4和PTK6可以克服对PAK4的耐药性。这些观察结果值得对部分BLCA患者进行临床研究。与单独使用任一药物相比，激酶抑制剂（vandetanib和dasatinib）的联合治疗均显示出更高的敏感性。因此，PAK4对于在其肿瘤中具有扩增和/或过表达的PAK4的一部分MIBC患者可能具有治疗作用。我们的结果还表明，联合抑制PAK4和PTK6可以克服对PAK4的耐药性。这些观察结果值得对部分BLCA患者进行临床研究。与单独使用任何一种药物相比，激酶抑制剂（vandetanib和dasatinib）的联合治疗均显示出更高的敏感性。因此，PAK4对于在其肿瘤中具有扩增和/或过表达的PAK4的一部分MIBC患者可能具有治疗作用。我们的结果还表明，联合抑制PAK4和PTK6可以克服对PAK4的耐药性。这些观察结果值得对部分BLCA患者进行临床研究。