P21-Activated Kinase Signaling in Cancer Biology

P21-activated kinases (PAKs) comprise a family of serine/threonine kinases that function downstream of the Rho GTPases RAC1 and CDC42 to regulate cytoskeletal dynamics, gene transcription, cell proliferation and survival. Aberrant PAK signalling has been implicated in multiple hallmarks of cancer, including enhanced motility, resistance to apoptosis, metabolic reprogramming and evasion of immune surveillance. Among the six isoforms, PAK1 and PAK4 are most frequently dysregulated in solid tumours, where they engage canonical pathways such as PI3K/AKT, MAPK/ERK and NF-κB to drive tumour initiation, progression and metastasis. Emerging evidence further connects PAK activity to metabolic control, hormone-therapy resistance and modulation of the tumour microenvironment, underscoring its appeal as a therapeutic target.

Research from Nature Portfolio

Recent studies have elucidated a novel PAK4-NCoR1 axis that links kinase activity to lipid metabolism in hepatic and cancerous tissues. PAK4 phosphorylates the nuclear receptor corepressor NCoR1, enhancing its interaction with PPARα and thereby repressing fatty acid β-oxidation and ketogenesis. This mechanism contributes to hepatic steatosis and provides a metabolic advantage to hepatocellular carcinoma cells under nutrient-rich conditions. Genetic ablation or pharmacological inhibition of PAK4 restores ketone body synthesis and attenuates tumour-associated lipid accumulation. In parallel, the orally bioavailable compound KPT-9274 has been shown to reduce steady-state PAK4 levels in triple-negative breast cancer cells, inducing apoptosis and suppressing tumour growth in murine models. These findings validate PAK4 as a dual regulator of metabolism and cell survival in diverse cancer contexts.

P21-Activated Kinase Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in p21-activated kinase signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

P21-activated kinase (PAK): Family of serine/threonine kinases activated by RAC1/CDC42 that regulate cytoskeletal architecture, cell cycle and survival.

Nuclear receptor corepressor 1 (NCoR1): Transcriptional corepressor that binds nuclear receptors such as PPARα to inhibit gene expression.

Peroxisome proliferator-activated receptor alpha (PPARα): Nuclear receptor governing fatty acid metabolism and ketogenesis.

Ketogenesis: Metabolic pathway in the liver that converts fatty acids into ketone bodies under low-glucose conditions.

Syngeneic mouse model: Experimental system where tumour cells are implanted into genetically identical mice to preserve intact immune interactions.

CDK4/6 inhibitor: Drug class targeting cyclin-dependent kinases 4 and 6 to block G1–S phase transition in proliferating cells.

Cytotoxic CD8+ T cell: Immune cell subset expressing CD8 that mediates antigen-specific killing of tumour or infected cells.

References

1. p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1. Nature Communications (2023).
2. Inhibition of P21-activated kinases 1 and 4 synergistically suppresses the growth of pancreatic cancer by stimulating anti-tumour immunity. Cell Communication and Signaling (2024).
3. Pak1 pathway hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. npj Breast Cancer (2023).
4. p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway. Oncotarget (2014).
5. A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth. Scientific Reports (2017).