These findings highlight a central role for CXCR2-mediated signaling in the development of radioresistance in HPV-negative HNSCC cells.

In this study, in addition to the induction of apoptosis, the use of PARPis (olaparib and niraparib) as maintenance therapies inhibited cell proliferation by causing cellular senescence to exert potent anticancer effects on Capan-1 (BRCA mutated) and PANC-1 (BRCA wild-type) cells...The inhibition of Bcl-2 through the sequence-dependent combination of navitoclax enhanced the anticancer effects of PARPis by removing senescent cells. Collectively, data from our study demonstrate that the clinical application of PARPis as maintenance therapy could be achieved through the induction of cellular senescence. Furthermore, sequence-dependent combination with senescence-targeting drugs can potentiate pancreatic cancer treatment effects of PARPis regardless of the BRCA status.

These findings establish XZ739 as a promising therapeutic candidate for BCL-XL-dependent CCA, highlighting its translational potential for rational combination with chemotherapy to overcome resistance while mitigating hematologic toxicity.

Since ABT-263 is unlikely to be approved for the clinical treatment of solid tumors due to both on-target (thrombocytopenia) and off-target (neutropenia) toxicities, the few studies indicating improved radiosensitivity with ABT-199 (venetoclax) are intriguing, suggesting that targeting of Bcl-xL may not be a strict requirement for the combination strategy. Finally, it is worth noting that senolytic agents have the potential to protect normal tissue from radiation-induced damage, which may prove to be the most clinically relevant observation for this class of drugs.

The combination of rhArg and ABT263 enhanced apoptosis and cell cycle arrest, demonstrating a potential broad-spectrum antitumor strategy.

Morusin induces CRC cell senescence via the DNMT1/CDK2/p53 axis, and renders the cells vulnerable to senolytic agents. This study not only broadens the development and utilization of morusin but also provides a novel sequential therapeutic strategy for combating CRC.

Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by in vitro organoid testing with the BCL-2/BCL-xL inhibitor navitoclax (IC 50 : 0.27 µM) and the MCL-1 inhibitor AZD-5991 (IC 50 : 0.060 µM). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with hypomethylating agents (HMAs) has improved treatment outcomes for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy and is increasingly used in the relapsed/refractory setting. Ex vivo treatment with the combination of navitoclax and SMAC mimetics further enhanced the eradication of VEN-HMA refractory blasts, although toxicity was also observed in healthy CD34+ cells. In conclusion, our integrative analysis identifies molecular signatures associated with primary VEN-HMA resistance and highlights BCL-2/BCL-XL inhibition and SMAC mimetics as therapeutic strategies to target resistance.

Brain irradiation induces liver proliferation, increased GFAP levels, and elevated ALT and AST activity, via mechanisms likely independent of senescence. Future investigation of blood GFAP levels is needed to determine whether the enhanced hepatic GFAP levels originate from the brain.

Finally, we show that a combination of irradiation with Navitoclax enhances cancer cell apoptosis in an orthotopic xenograft DMG model. Together, the data demonstrate that ionising irradiation leads to senescence induction in H3K27M-altered human DMG cell lines, making them particularly sensitive to apoptosis through Bcl-xL inhibition.

Our previous study demonstrated that cisplatin (CDDP) induced ESCC cell senescence, and senescent cells promoted the aggressive behaviors of neighboring cancer cells through the senescence-associated secretory phenotype (SASP). Mechanistically, the enhanced interaction between BCL-XL and pro-apoptotic effector protein BAX conferred apoptosis resistance in senescent ESCC cells, and ABT-263 treatment disrupted this interaction to activate apoptosis. Overall, our data indicate that CDDP-induced senescent ESCC cells could be eliminated using senolytic drugs that target BCL-XL, and thus senolytic therapy could be a potential effective strategy for improving chemotherapeutic efficacy in ESCC.