CHEK1 (Checkpoint kinase 1)

P1/2, N=120, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2027 --> Mar 2029 | Trial primary completion date: Mar 2026 --> Mar 2028

Whereas p53 KO organoids are sensitive to the combined inhibition of ATM and PARP, acid adaptation partially rescues this phenotype, increasing treatment resistance in a manner partially restored by the combined inhibition of pH-regulatory transporters. We conclude that p53 loss rewires acid-base homeostasis and that microenvironment acidity limits treatment response in p53-deficient PDAC, possibly by increasing cancer cell pH homeostasis capacity.

PRS assessment identified four PRSs with good discriminatory power (AUC > 0.690), with PGS003738 showing the highest performance (AUC = 0.702, top decile OR = 3.57). These findings highlight the need for population-specific genetic studies to improve breast cancer risk stratification in Arab populations.

Pairwise drug combinational antiproliferative assays revealed that 10h and niraparib synergistically enhanced antiproliferative effects against Granta-519. These results suggested that 10h holds promise for further development as a lead compound for the design of ATR kinase-targeted therapies.

Docking simulations suggested potential binding modes for 11c, which aligned closely with findings from enzymatic examinations. The in silico physicochemical properties, drug-likeness metrics, and ligand efficiency of 11c appeared to be promising.

Since CSEN correlates with aging, it is reasonable to conclude that exogenous genotoxic pollutants contribute significantly to the aging process through CSEN induction. In light of these findings, it is deduced that reducing genotoxin exposures and using "rejuvenation" supplements (senotherapeutics) are reasonable strategies to counteract cellular senescence and the aging process.

Oxaliplatin (OXA) is combined with the fluoropyrimidine (FP) drug 5-fluorouracil (5-FU) in the FOLFOX regimen used to treat advanced colorectal cancer (CRC)... Our results demonstrate that OXA synergizes with CF10 more effectively than with 5-FU through enhanced replication stress in both WT and TP53-null cells by causing greater Top1-mediated DNA double-strand breaks. Our studies provide a foundation for further testing of this combination in an orthotopic liver metastatic setting and eventual clinical development.

Together, these findings suggested that SL has chemopreventive efficacy as well as strong anti-proliferative and pro-apoptotic activities against lung cancer.

Isoform-specific knockdown of TTLL12 and HM13 significantly decreased the viability of two EAC cell lines, sensitized EAC cell lines to standard-of-care chemotherapy agents (paclitaxel and carboplatin) with synergy, and inhibited EAC cell migratory potential. In addition, HM13 isoform knockdown increased the response to an anti-PD-L1 agent, avelumab, in EAC cells, suggesting a role for isoform switching in immunosuppression. Taken together, study results suggest that isoform switching may provide novel insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC treatment or prevention.

Our study identifies SMC4 as a regulator that promotes radioresistance and potentially modulates the tumor immune microenvironment in cervical cancer, likely by coordinating DNA damage repair and activating the SMAD3-NF-κB pathway. These findings suggest that SMC4 could be a potential therapeutic target for radiosensitization and a candidate biomarker for patient stratification.

Lastly, we touch upon the new nanocarrier-based delivery approaches that enhance pharmacokinetics, target resistant tumor niches, and expand the possibilities for combinatorics with immunotherapy and radiotherapy. Collectively, these findings provide a guide to the implementation of next-generation DDR inhibitors and nanomedicines to deliver a more accurate, durable, and context-specific cancer therapy.

In summary, PA binds to human DNA Topoisomerase IIα/β, then induces Topo/ATM/ATR/CHK signaling pathways, which cleave PARP and γ-H2AX, leading to p-p53 activation and cell cycle arrest at the G2/M phase in HSC-3 cells. It is suggested that PA could develop a novel therapeutic agent against OSCC cells in the future.