Carfilzomib synergized with BCL2 family protein inhibitors (navitoclax or AZD5991), suggesting that drug combinations could be used to reduce the dose of each drug to minimize toxicity. Notably, thymic carcinomas differed from squamous cell carcinomas in other organs by higher levels of β5i (PSMB8) and constitutive proteasome β5 (PSMB5). We hypothesize that TC (and probably many TH) are uniquely suited for treatment with proteasome inhibitors alone or in combination with selective BH3 mimetics.

Inhibiting Rap1 signaling results in increased sensitivity to the BCL2/BCL-XL inhibitor navitoclax. Our study provides insights into the immune microenvironment of pediatric hematologic malignancies, forming the basis for identifying potential (immuno) therapeutic targets and risk stratification for treatment.

High-risk HCC responded poorly to sorafenib and transarterial chemoembolization (TACE) but sensitively to agent ABT-263 in silico, in vitro, and in vivo experiments. Interpretability analysis revealed consistent biomarker contributions in both signatures. Conclusively, the dual signatures show promise for HCC risk stratification, pending external validation.

The FRET-HBTDS method was performed on the FRETscope with a 20× objective for the cells co-expressing CFP-Bcl-xL and YFP-Bak to assess the action of eight compounds (A1331852, S63845, AC, DSF/Cu, Met, REGO, SOFA, ABT199) on the interaction between Bcl-xL and Bak. Our data firmly demonstrate that A1331852 unlocks the binding state of Bcl-xL and Bak, while DSF/Cu modifies the structure of the Bcl-xL-Bak complex. These findings demonstrate that FRET-HBTDS can be used to assess the efficacy of a drug by revealing the binding state and complex molecular structure of the target proteins using FRET technology in living cells, which may be a potential targeted drug screening method.

Based on the rapid recovery of transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-XL in peripheral leukocytes, the RP2D of DT2216 is 0.4 mg/kg IV BIW. (NCT04886622).

DIS accelerates the malignant progression of shRB1 CRPC, mediated by tumorigenic SASP, especially IL-20 enrichment. Notably, we identifies a novel FOXA1-IL-20-IL20Rβ axis that drives M2-like macrophage polarization and contributes to tumor aggressiveness and docetaxel resistance. Importantly, senolytic agent ABT-263 not only selectively eliminated shRB1-DIS cells but also restricted expression of tumorigenic SASPs, thereby restoring sensitivity to docetaxel. Wherein, IL-20 is inhibited through its interaction with ABT-263. These results provide a novel mechanistic rationale for using senolytic therapies to mitigate SASP-driven malignancy and improve treatment response in RB1-deficient CRPC.

Small-molecule inhibitors such as ABT-737 and Navitoclax, kinase inhibitors targeting NF-κB (Nuclear Factor kappa-light-chain-enhancer of Activated B Cells) and JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) pathways, and natural compounds including fucoxanthin, peridinin, and thymoquinone have demonstrated the ability to overcome apoptosis resistance in preclinical models. Recent strategies combining MCL-1 inhibitors with antiretroviral therapy or immune checkpoint blockade further highlight the translational potential of targeting BCL-2 pathways. Collectively, the evidence positions the BCL-2 family as a critical determinant of deltaretroviral persistence and leukemogenesis, and as a promising therapeutic axis for the development of novel treatments for HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and BLV-associated leukosis.

P1, N=20, Not yet recruiting, The Second Hospital of Hebei Medical University; The Second Hospital of Hebei Medical University

CEP-1347 induced cellular senescence in OCCC cells with wild-type TP53. The combination of CEP-1347 with senolytics, such as navitoclax, represents a rational strategy to ensure the selective elimination of senescent OCCC cells and enhance therapeutic efficacy.

Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies.

To inhibit SRC activity, natural compounds (e.g., gossypol, bufalin, verrucarin A) and synthetic small molecules (e.g., SI-2, SI-12, MCB-613) have been developed, demonstrating preclinical efficacy across several human diseases...This review summarizes current knowledge of SRC biology in benign gynecologic disorders, outlines their mechanistic roles in disease progression, and highlights opportunities for clinical translation. Targeting SRCs may ultimately represent a novel, non-hormonal, fertility-preserving therapeutic strategy in women's health.

Using CRISPR-based genome-wide perturbation screens, we investigated the genetic dependencies of venetoclax and the BCL2/BCL2L1 dual inhibitor AZD4320. Accordingly, in AML patient samples we found reduced expression of the respective m6a or NuRD complexes was significantly associated with monocytic differentiation and ex vivo resistance to the same drugs. These findings provide critical insights into previously undescribed mechanisms of BCL2 family inhibitor resistance in AML.