Wang, Congli

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a mainstay therapy for homologous recombination (HR)-deficient cancers; however, resistance remains a major clinical challenge. Previously, through a genome wide CRISPR screen, we identified ZNF251 haploinsufficiency as a novel driver of PARPi resistance. In BRCA1 -mutant ( BRCA1 mut ) cells, ZNF251 deficiency led to HR hyperactivation, conferring PARPi resistance that could be reversed by RAD51 inhibition. In this study, we further show that ZNF251 deficiency induces replication stress and a pseudo-senescence state, in which cells exhibit molecular and phenotypic markers of senescence while retaining proliferative capacity. Because senomorphic and senolytic therapies can target senescent cells, we tested whether these approaches could overcome PARPi resistance in ZNF251 -deficient breast cancer cells. Critically, targeting this senescence-like state with either senomorphic agents, such as cytokine inhibitors, or senolytic agents, such as BCL-2 and BCL-XL inhibitors, overcame PARPi resistance ex vivo and in vivo . Importantly, pseudo-senescence was also observed in other PARPi-resistant contexts driven by HR hyperactivation, including 53BP1 - and Shieldin -mutant cells, suggesting that it may represent a broader mechanism underlying PARPi resistance in breast cancer. Furthermore, in two olaparib-resistant, BRCA -mutant triple-negative breast cancer organoid models, treatment with DT2216, a BCL-XL–targeting PROTAC, sensitized both models to olaparib. Together, our work defines a novel pathway linking HR hyperactivation, replication stress, and pseudo-senescence, and positions both senomorphic and senolytic therapies as promising strategies to overcome PARPi resistance in BRCA1 mut breast cancer. Highlights ZNF251 deficiency drives PARP inhibitor resistance through HR hyperactivation, replication stress, and pseudo-senescence in BRCA1 -mutant breast cancer. Senomorphic and senolytic therapies overcome PARP inhibitor resistance in vitro , in vivo , and in patient-derived organoid models. Pseudo-senescence represents a shared vulnerability of HR-hyperactivated PARPi-resistant cancers and can be therapeutically targeted.

The newly proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification of lung adenocarcinoma has emphasized the prognostic significance of histological subtyping. In this study, 2 surgical pathologists reevaluated 49 consecutive cases of invasive primary pulmonary adenocarcinomas; histological subtyping was performed according to the IASLC/ATS/ERS classification. The 2 reviewers agreed on the predominant pattern in 23 out of 32 independently reviewed cases (71.9%, k = 0.628, 95% confidence interval = 0.442-0.815). Postconsensus, a complex glandular pattern consisting of fused, closely packed glands and cribriform architecture was identified in 9 of 49 (18%) cases. This pattern has a strong association with lymphovascular invasion (78%; P = .0091), high mitotic activity (89%), and higher tumor stage (78%). Frequent association of complex glandular pattern with poor prognostic factors and its overlap with acinar pattern warrant a more detailed description of this pattern in the classification system and a large-scale study to evaluate its prognostic significance.