p21-activated kinases (Paks) are positioned at the nexus of several oncogenic signaling pathways. Overexpression or mutational activation of Pak isoforms is frequently seen in various human tumors, and recent data suggests that excessive Pak activity drives many cellular processes that are the hallmarks of cancer. In this review, we discuss the mechanisms of Pak activation in cancer, the key substrates for this family of kinases that mediate their developmental and oncogenic effects, and how small molecule inhibitors of these enzymes might best be developed and deployed in the treatment of cancer.

Highlights d EZH2 inhibitor sensitizes CARM1-high EOC cells to PARP inhibitor d EZH2 inhibitor upregulates MAD2L2 and NHEJ activity in CARM1-high EOC cells d EZH2 and PARP inhibitor combination causes mitotic catastrophe d EZH2 and PARP inhibitors are synergistic in suppressing CARM1-high EOCs in vivo

p21-activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors, and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents. Given the central role of PAK1 in vital signaling pathways, future clinical development of PAK1 inhibitors will require careful investigation of their safety and efficacy.

Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1. In this work, we explore the effects of PAK inhibition on RAC1P29S signaling in zebrafish embryonic development, in the proliferation, survival, and motility of RAC1P29S-mutant human melanoma cells, and on tumor formation and progression from such cells in mice. We report that RAC1P29S evokes a Rasopathy-like phenotype on zebrafish development that can be blocked by inhibitors of PAK or MEK. We also found and that RAC1 mutant human melanoma cells are resistant to clinical inhibitors of BRAF but are uniquely sensitive to PAK inhibitors. These data suggest that suppressing the PAK pathway might be of therapeutic benefit in this type of melanoma.