Loss of phosphatase and tensin homolog (PTEN) impairs DNA double-strand repair and confers sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPis). However, PARPis also hyperactivate the MAPK and PI3K/AKT/mTOR pathways in PTEN-deficient endometrial carcinoma (EC), which allows the emergence of PARPi resistance. BCL-2–associated death promoter (BAD), integrates the common cell survival effects of the RAS/MEK/MAPK and PI3K/AKT/mTOR pathways. Herein, it was observed that increased BADSer99 (BADS99) phosphorylation in EC cells was significantly associated with PTEN-deficient status. Forced expression of phosphorylation deficient human BADS99A in PTEN-deficient EC cells significantly increased CASPASE 3/7 activity and decreased EC cell viability. Using NPB as a pharmacological inhibitor of pBADS99 phosphorylation, it was demonstrated that NPB synergized with PARPis (Olaparib, Rucaparib and Talazoparib) to enhance PARPi IC₅₀ up to 60-fold and decreased survival, foci formation, and growth in 3D ex vivo culture of PTEN-deficient EC cells. Combined NPB-PARPi treatment of PTEN-deficient EC cells stimulated apoptosis and promoted DNA damage by impairment of homologous recombination. Using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonuclease system it was demonstrated that deletion of PTEN in PTEN replete EC cells enhanced the efficacy of combined NPB-PARPi treatment. Furthermore, combined inhibition of BADS99 phosphorylation and PARP ablated xenograft growth of PTEN-deficient EC cells. Similarly, a combination of NPB and PARPis significantly suppressed the growth of PTEN deficient patient-derived EC organoids. Hence, combined inhibition of BADS99 phosphorylation and PARP represents a rational and efficacious strategy to improve the prognosis of recurrent EC patients.

Background: Poly (ADP-ribose) polymerase inhibitors (PARPis) have been approved for the treatment of recurrent epithelial ovarian cancer (EOC), regardless ofBRCAstatus or homologous recombination repair deficiency. However, the low response of platinum-resistant EOC, the emergence of resistance inBRCA-deficient cancer, and therapy-associated toxicities in patients limit the clinical utility of PARPis in recurrent EOC.Methods: The association of phosphorylated (p) BADS99 with clinicopathological parameters and survival outcomes in an EOC cohort was assessed by immunohistochemistry. The therapeutic synergy, and mechanisms thereof, between a pBADS99 inhibitor and PARPis in EOC was determined in vitro and in vivo using cell line and patient-derived models.Results: A positive correlation between pBADS99 in EOC with higher disease stage and poorer survival is observed. Increased pBADS99 in EOC cells is significantly associated withBRCA-deficiency and decreased Cisplatin or Olaparib sensitivity. Pharmacological inhibition of pBADS99 synergizes with PARPis to enhance PARPi IC₅₀and decreases survival, foci formation, and growth in ex vivo culture of EOC cells and patient-derived organoids (PDOs). Combined inhibition of pBADS99 and PARP in EOC cells or PDOs enhances DNA damage but impairs PARPi stimulated DNA repair with a consequent increase in apoptosis. Inhibition of BADS99 phosphorylation synergizes with Olaparib to suppress the xenograft growth of platinum-sensitive and resistant EOC. Combined pBADS99-PARP inhibition produces a complete response in a PDX derived from a patient with metastatic and chemoresistant EOC.Conclusions: A rational and efficacious combination strategy involving combined inhibition of pBADS99 and PARP for the treatment of recurrent EOC is presented.

Uterine corpus endometrial carcinoma (UCEC) poses significant clinical challenges due to its high incidence and poor prognosis, exacerbated by the lack of effective screening methods. The standard treatment for UCEC typically involves surgical intervention, with radiation and chemotherapy as potential adjuvant therapies. In recent years, immunotherapy has emerged as a promising avenue for the advanced treatment of UCEC. This study employs a multi-omics approach, analyzing RNA-sequencing data and clinical information from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and GeneMANIA databases to investigate the prognostic value of MutL Homolog 1 (MLH1) gene expression in UCEC. The dysregulation of MLH1 in UCEC is linked to adverse prognostic outcomes and suppressed immune cell infiltration. Gene Set Enrichment Analysis (GSEA) data reveal MLH1’s involvement in immune-related processes, while its expression correlates with tumor mutational burden (TMB) and microsatellite instability (MSI). Lower MLH1 expression is associated with poorer prognosis, reduced responsiveness to Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors, and heightened sensitivity to anti-cancer agents. This comprehensive analysis establishes MLH1 as a potential biomarker for predicting prognosis, immunotherapy response, and drug sensitivity in UCEC, offering crucial insights for the clinical management of patients.

Under the 9th edition AJCC/UICC staging system, Stage IB nasopharyngeal carcinoma (NPC, T1-2N1M0) represents a biologically heterogeneous population for wh