P21-activated kinase 1 (PAK1), a serine/threonine kinase overexpressed in various malignancies, plays a central role in cytoskeletal remodeling, cell motility, and survival; however, the specific molecular mechanisms by which it maintains the stability of cancer-driving transcripts in CRC have remained elusive. In a recent study published in Genes & Diseases , researchers from the Jiangsu Institute of Cancer Research and the Affiliated Cancer Hospital of Nanjing Medical University identified a novel oncogenic mechanism of PAK1 and its significance in the growth and metastasis of CRC.
Using CRISPR/Cas9-mediated PAK1 knockout (KO) and lentiviral-mediated PAK1 overexpression (OE) cell lines, the authors demonstrated that targeting PAK1 effectively inhibits proliferation, migration, and invasion in vitro . GSEA results revealed significant enrichment in PI3K/AKT/mTOR signaling-related pathways, while further experimental validation indicated that PAK1 promotes CRC progression via the mTOR-S6K pathway.
Additionally, using data-independent acquisition (DIA) proteomic analysis, the authors observed a significant downregulation in the expression of PRSS3, CD44, PROS1, and SAA1 proteins in the PAK1 KO group. The concurrent inhibition of CD44 and SAA1 mRNAs suggested that PAK1 promotes CRC progression by preventing mRNA decay. Actinomycin D experiments confirmed the critical role of PAK1 in mediating the mRNA stability of these oncogenic genes.
To investigate whether PAK1 inhibition reverses chemoresistance, the authors used PF3758309 (PF-309), a small-molecule ATP-competitive inhibitor, to block PAK1 activity. They demonstrated that pharmacological blockade of the PAK1 kinase domain triggers rapid mRNA decay and suppresses multiple oncogenic signaling pathways. Furthermore, PAK1 inhibition exhibits a potent synergistic effect with oxaliplatin, significantly enhancing chemotherapeutic efficacy and inducing tumor regression in patient-derived organoids and in vivo models by accelerating mRNA degradation and halting protein synthesis.
In conclusion, this study establishes that PAK1 drives CRC progression by stabilizing the mRNA of oncogenic factors—specifically PRSS3, CD44, PROS1, and SAA1. Its genetic and pharmacological inhibition promotes the degradation of these transcripts, establishing PAK1 as a high-value therapeutic target for sensitizing colorectal tumors to standard-of-care treatments and overcoming chemoresistance.
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