We supposed that 14α-hydroxymatrine of compound Kushen injection might be a reversible allosteric inhibitor of PAK1. This study used modern technologies and methods to study the active components of traditional Chinese medicine, which laid a foundation for the development and utilization of natural products and the search for new treatments for pancreatic cancer.

Our findings elucidate the effect of PAK4 on enhancing bone formation in osteoblasts and its pivotal role in the anabolic activity of PTH mediated through its interaction with β-catenin. These insights improve the understanding of the mechanisms underlying PTH activity and should inform the development of more effective and safer osteoporosis treatments.

We identified a class I PI3K inhibitor, pictilisib and p21 activated kinase (PAK) inhibitor, PF-3758309 as the top combination due to high synergy in cell viability assays. The inhibitor combination promoted cell cycle arrest and apoptosis in mouse merlin-deficient Schwann (MD-SCs) cells and cell cycle arrest in human MD-SCs. This study identifies the PI3K and PAK pathways as potential targets for combination drug treatment of NF2-related schwannomatosis.

PAK1 expression was significantly correlated with worse prognosis in CRCs patients. In addition, PAK1 expression was significantly correlated with a low immunoscore and high expression of HIF-1α and pFOXO1 in CRCs.

PAK inhibitors, PF3758309 (PF) and FRAX597, could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition. These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin. Collectively, our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.

Co-crystallization revealed that PAK5-Af17 bound in the P+1 pocket of PAK5, locking the kinase into a partial activation state. This mechanism of inhibition indicates that another class of kinase inhibitors is possible.

In conclusion, our results suggest the simultaneous blockade of mTOR and Pak pathways as a promising alternative therapeutic strategy for patients affected by KRAS-mut colorectal cancer.

Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid β-oxidation and ketogenesis.

In vivo, both CSF2 silencing and PF3758309 suppressed PAK1-driven tumor proliferation and angiogenesis. Conclusively, the nuclear entry of overexpressed/activated PAK1 endows myxofibrosarcomas with pro-angiogenic function, highlighting the vulnerable PAK1/STAT5B/CSF2 regulatory axis.

Our findings indicated that instead of treatment with Sorafenib alone, the combination of ATRA and Sorafenib provides a more effective treatment for HCC patients. Video Abstract.

Finally, treatment with Pak1 inhibitors, PF-3758309 (PF309) and NVS-PAK1-1, restored cell sensitivity to fulvestrant and abemaciclib of MCF7-FAR and T47D-FAR cells, both in vitro and in vivo. In conclusion, our data suggested a pivotal role for Pak1 in resistance to ET and CDK4/6i in ER+ breast cancers. These data might promote the rationale for the development of novel Pak1 inhibitors for treatment of patients with ER+ BC progressing on ET plus CDK4/6i.

In the current review, we describe the pathophysiology and current treatment guidelines of PCa, present group-I PAKs as a potential druggable target to treat mPCa patients, and discuss the various ATP-competitive and allosteric inhibitors of PAKs. We also discuss the development and testing of a nanotechnology-based therapeutic formulation of group-I PAK inhibitors and its significant potential advantages as a novel, selective, stable, and efficacious mPCa therapeutic over other PCa therapeutics in the pipeline.

Therefore, future studies employing in vitro and in vivo steps, using murine and human enterocytes and rodents submitted to ulcerative colitis and CAC models are incentivized by the data gathered here, mostly in vitro studies, before clinical trials. Therefore, the perspective presented here points to an interesting path in the search for a drug useful in inflammatory and neoplastic intestinal diseases, which may have ARC as a prototype, acting on a target not yet explored clinically.

The feedback loop LINC00467/miR-485-5p/PAK1 was identified, which was responsible for inducing melanoma deterioration. LINC00467 stimulates proliferation, migration and invasion capacities of melanoma via targeting miR-485-5p to upregulate PAK1, which provides potential targets for treatment of melanoma.

This study showed that PAK1 inhibition impedes the proliferation, migration, and invasion of glioma cells.

Moreover, we find that PAK5 protein level in MDS is significantly higher than leukemia, and the data of 2095 leukemia samples from 'BloodSpot' database shows that PAK5 mRNA level in MDS is also increased obviously. Taken together, our findings suggest that PAK5-targeted strategies in clinical therapy have a potential value on MDS intervention.

Our data reveal a unique dependency of mesenchymal CRC and provide a rationale for PAK2 inhibition to target this aggressive subgroup of colorectal cancer.

This study demonstrates that the PAK4 regulates the biological behaviors of OSCC by PI3K-AKT signaling pathway, and these findings might provide a novel strategy for OSCC treatment.

Mechanistically, PIK3CD regulates the activity of p21 activated kinase (PPAK3) and plecstrin 2 (PLEK2) through axonogenesis pathway. The findings provide a novel mechanism of PIK3CD-mediated GBM development and suggest PIK3CD might be a target of GBM.

Moreover, SOX2 activated the expression of DEK, and silencing DEK attenuated the malignant behaviors of LSCC cells. In conclusion, PAK2 could bind to the transcription factor SOX2 and thus activate the expression of DEK, thereby driving the malignant phenotypes of LSCC cells both in vivo and in vitro.

The present data suggested that the upregulation of circ_0001789 was associated with the progression of GC and with poor prognosis in patients with GC, and that miR-140-3p/PAK2 served as the downstream axis to mediate the oncogenic effect of circ_0001789.

In vitro studies showed that Rac1 knockdown decreased the expression of EMT markers including PAK1 and Snail in hypoxia-induced Hep3B cells and suppressed the migration and invasion of hypoxia-induced HCC cells. Rac1 may be a potential therapeutic target for inhibition of EMT process through the inhibition of PAK1 and Snail in HCC.

Exosomal miR-485-3p delivered by normal pancreatic ductal epithelial cells into PC cells inhibits PC metastasis by directly targeting PAK1. The restoration of miR-485-3p by exosomes or some other vehicle might be a novel approach for PC treatment.

"Background: The mTOR inhibitor, Everolimus (EVE), is FDA-approved for the treatment of advanced PNENs on the basis of delay of progression... Our study demonstrates that PAK4-high/NAMPT-high PNENs are associated with distinct molecular and immune profiles. While the dual blockade of PAK4 and NAMPT has been reported to enhance the efficacy of EVE in PNENs, whether such a blockade would enhance the efficacy of immunotherapeutics warrants further investigation."

A decrease in PAK4 activity increases immune activation and vascularity, which increases CD8 lymphocyte infiltration into the tumor. Therefore, targeting PAK4 may improve the response of human PC to immunotherapy.

PAK4 could be considered as a prognostic and immunotherapeutic marker for some types of malignant tumor.

In conclusion, GI cancers are very diverse at the molecular level. However, the shared mutations and protein pathways might be used to understand better and reveal diagnostic/prognostic or drug targets.

Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL.

Furthermore, autophagy plays an important role in PDA immune evasion, and accumulating evidence has pointed to a connection between PAK and cancer cell autophagy. In this literature review, we aim to summarize currently available studies that have assessed the potential connection between PAK, autophagy and immune evasion in PDA biology to guide future research.

Moreover, SOX2 activated the expression of DEK, and silencing DEK attenuated the malignant behaviors of LSCC cells. In conclusion, PAK2 could bind to the transcription factor SOX2 and thus activate the expression of DEK, thereby driving the malignant phenotypes of LSCC cells both in vivo and in vitro.

We additionally observed that the suppression of PAK2 via knockdown or pharmacological targeting with PAK inhibitors markedly restored the response of osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. In conclusion, these results indicated that the PAK2-mediated activation of β-catenin is important for osimertinib resistance and targeting the HER3/PAK2/β-catenin pathway has potential therapeutic value in NSCLCs with acquired resistance to osimertinib.

The combined immunotherapy elicits robust anticancer immunity, thus showing great promise for fighting cancers. Our work opens a new avenue to simultaneously boost intratumoral infiltration and immune activation for sensitized cancer immunotherapy.

Our study provides a rationale for further research on the prognostic and therapeutic potential of PAKs in human tumors.

Mechanistically, the disturbed cytokine receptor by reducing activity of PPTLS-APE1/Ref-1 inhibited inflammatory signaling leading to the inactivation of the p21-activated kinase 1-mediated signal transducer and activator of transcription 3/nuclear factor-κB axis in tumor tissues. These results suggest that the regulation of inflammatory signaling with adenoviral-mediated PPTLS-APE1/Ref-1 in tumors modulates the secretion of pro-inflammatory cytokines in TME, thereby inhibiting aggressive cancer cell progression, and could be considered as a promising and safe therapeutic strategy for treating TNBCs.

Cox regression analysis explained that PAK4 expression was associated with the prognosis of NSCLC patients (P = .024; HR, 3.104; 95% CI, 1.164-8.278). In a word, PAK4 was highly expressed in NSCLC tissues and could act as a prognostic factor for NSCLC patients.

Furthermore, the PAK1 inhibitor IPA-3 exerted an anti-tumor effect and its combination with ibrutinib exhibited a synergistic effect in ibrutinib-sensitive and -resistant cells. These findings suggest the oncogenic role of PAK1 in CLL progression and drug resistance, highlighting PAK1 as a potential diagnostic marker and therapeutic target in CLL including ibrutinib-resistant CLL.

This study firstly confirmed the role and mechanism of SNHG16 in the occurrence and development of melanoma. Therefore, SNHG16 may become a key point in the diagnosis, prognosis and treatment of melanoma patients in the future.

Knocking down the expression of PAK1 promotes the formation of polyploid DNA and induces AMKL cell apoptosis. The above findings indicate that inhibiting the activity of PAK1 may control AMKL effectively.

Additionally, this combination sensitized colon cancer cells to ionizing radiation that resulted in inhibition of cell growth. Significance: Collectively, our findings show for the first time that cotreatment of IPA-3 with PF-3758309 exhibits superior inhibitory effects on colon carcinoma cell growth via inducing DNA damage-related cell death and also enforces a cell cycle arrest.

Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing.