The ability of tumor cells to tolerate DNA damage limits the efficacy of many anticancer therapies. Our study reveals that pancreatic cancer cells enforce this resistance by sustaining expression of DNA damage response (DDR) genes through Class I histone deacetylases (HDACs). HDACs maintain genome-wide acetylation patterns required for efficient recruitment of the transcriptional machinery to DDR genes. Pharmacological HDAC inhibition disrupts this process and sensitizes pancreatic cancer cells to diverse DNA-damaging agents. To overcome systemic toxicity that limits translational potential, we further establish a bottlebrush prodrug nanoparticle platform that enables tumor-selective HDAC inhibition. Given the central role of the DDR in cancer, targeting HDAC-mediated DDR regulation through drug combinations and precision delivery may have broad therapeutic relevance across cancer types.

Exploratory in silico drug-response analyses identified differential predicted responses to entinostat, linsitinib, and VE-822 according to risk status and DUBR expression. This internally validated signature may support exploratory prognostic risk stratification of LSCC within the analyzed TCGA-derived cohort and may highlight DUBR as a candidate molecule for further biological investigation. Further validation in independent external cohorts and dedicated disulfidptosis functional assays is required before these findings can be considered generalizable.

In vivo, we confirmed that entinostat treatment increased the expression of immunecheckpoint ligands and antigen presentation machinery in Myc-driven tumors in a Rb1/Trp53/MycT58A (RPM) SCLC mouse model, while shifting tumors from a neuroendocrine (NE)-high to a NE-low phenotype, and was associated with increased T-cell infiltration Notably, combining entinostat with anti-PD-1 immunotherapy suppresses tumor growth and significantly prolonged survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.

Comparative pathway analysis identified preferential de-repression of a G2/M checkpoint gene program in 105C spheroids upon Entinostat treatment when compared directly to the KOC-7c spheroids. Our results suggest that the utility of HDACi in OCCC is highly context-dependent.

Exploratory drug-response modeling with pRRophetic suggested lower estimated half-maximal inhibitory concentration (IC50) values for agents including MS-275 (entinostat), PF-4708671, and roscovitine in the high-risk group. The TIDE algorithm carries prognostic information in NSCLC beyond immunotherapy settings. The proposed TIDE-informed gene signature reproduced prognostic stratification across cohorts, suggesting potential applicability to a broader NSCLC population and supporting future personalized risk stratification.

Murine and human MDSC models treated with Entinostat revealed that the long non-coding RNA Malat1 downregulates pSTAT3 and decreases MDSC-mediated suppression of T cell proliferation...Collectively, our findings provide a multi-pronged mechanism of HDAC inhibition in MDSCs that inform the development of future rational combination therapies. HDAC1 inhibition in MDSCs increases Malat1 , decreases pSTAT3, induces apoptosis/cell cycle arrest, and decreases suppression of T cells.

Our findings reveal an epigenetic-Hippo-immunomodulatory axis in osteosarcoma that also extends to other sarcomas, providing a rationale for incorporating epigenetic preconditioning with immunotherapy to improve patient outcomes and pointing towards novel biomarkers for treatment guidance.

Leveraging scaffold hopping and structural optimization strategies, we developed fifteen indole-based derivatives utilizing vorinostat (SAHA) and entinostat as lead compounds. Mechanistic investigations of representative hydroxamate and benzamide derivatives corroborated their marked antiproliferative effects in HCT-116 cancer cells and manifested a favorable safety profile against the normal fibroblasts (WI-38). Altogether, these findings underscore the therapeutic potential of the identified potent compounds for combating cancer via HDAC1/6 inhibition.

P2, N=60, Recruiting, Hebei Medical University Fourth Hospital

In vivo, Entinostat suppressed tumor growth and consistently modulated the HDAC1/p53/AMPK/mTOR pathway. In conclusion, Entinostat exerts potent anti-tumor activity in SCLC by simultaneously inducing apoptosis and autophagy through epigenetic modulation of p53 via HDAC1 inhibition and subsequent regulation of the AMPK/mTOR axis.

P1/2, N=47, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2026 --> Feb 2027

Combination regimens such as retinoic acid with entinostat and doxorubicin achieve potent antitumor synergy in preclinical models. Notably, emerging methylation-based classifiers that identify retinoid-responsive triple-negative breast cancer subsets, together with the paradoxical pro-tumorigenic effects of stromal RARβ, underscore the novelty and translational significance of integrating tumor-intrinsic and microenvironmental determinants of retinoid sensitivity. Together, these approaches may help re-establish functional retinoid signaling and realize the therapeutic potential of retinoic acid in breast cancer.