Ovarian cancer remains the most lethal gynaecological malignancy, characterised by high mortality rates and the frequent occurrence of late-stage metastatic diagnoses.

While poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionised ovarian cancer treatment—particularly for patients harbouring BRCA1/2 mutations or deficiencies in homologous recombination (HR) repair—the emergence of PARPi resistance and the presence of HR-proficient tumours continue to limit their clinical benefit, underscoring the need for strategies to improve long-term outcomes.

In a recent study published in the Genes & Diseases journal, researchers from the Chinese Academy of Medical Sciences and Peking Union Medical College, Chinese Academy of Sciences, and Mayo Clinic demonstrated that targeting p21-activated kinase 1 (PAK1), a serine/threonine kinase implicated in tumour progression and cellular stress responses, enhances the therapeutic efficacy of PARP inhibition in ovarian cancer.

Using the cBioPortal database, the authors established that elevated PAK1 expression strongly correlates with poor overall survival in ovarian cancer patients.

Further investigation demonstrated a positive relationship between PAK1 activity and HR pathways.

Since PARP inhibitors exert their strongest anti-cancer effects in cells with defective HR repair, the researchers explored whether disrupting PAK1 could induce HR deficiency and thereby increase sensitivity to PARP-targeted therapies.

Using a combination of genetic and pharmacological approaches, the authors showed that PAK1 deficiency significantly impaired homologous recombination repair without affecting non-homologous end joining.

Functional DNA repair assays revealed reduced HR efficiency following PAK1 loss, indicating that PAK1—and importantly, its kinase activity—is required for optimal HR-mediated repair of double-strand DNA breaks.

Additionally, reduced RAD51 foci formation, a key marker of homologous recombination activity, further confirmed HR impairment.

When combined with the PARP inhibitor olaparib, PAK1 inhibition produced a pronounced anti-tumour effect.

Ovarian cancer cells with reduced PAK1 activity exhibited greater sensitivity to olaparib, accompanied by increased DNA damage accumulation, elevated replication stress, and enhanced activation of cell death pathways, resulting in substantially greater tumour cell killing than either treatment alone.

To evaluate the translational potential of this strategy, the authors employed IPA-3, an allosteric inhibitor of PAK1 kinase activity, and demonstrated that pharmacological blockade of PAK1 reproduced similar effects.

DNA fibre assays, chromatin fractionation, and transcriptomic analyses revealed that combining olaparib with IPA-3 increased replication stress, resulting in the accumulation of fatal double-strand breaks, as evidenced by elevated γ-H2AX levels and activation of apoptotic pathways.

To validate these in vitro observations, the researchers employed cell line-derived xenografts, patient-derived organoids, and patient-derived xenograft models.

Across all models, combination therapy with olaparib and IPA-3 synergistically suppressed ovarian tumour growth, reduced cellular proliferation, and enhanced apoptosis without exacerbating hepatotoxicity.

In conclusion, this study identifies PAK1 as a critical regulator of homologous recombination repair and a key determinant of PARP inhibitor sensitivity in ovarian cancer.

By impairing DNA repair, PAK1 inhibition enhances the anti-tumour activity of PARP inhibitors, leading to increased DNA damage and tumour cell death.

These findings highlight the potential of combining PAK1 and PARP inhibitors as a promising therapeutic strategy to overcome resistance and improve treatment outcomes in ovarian cancer.

Source: Compuscript Ltd