adavosertib (AZD1775)

In colorectal cancer organoids, 24 outperformed our prior PKMYT1 inhibitor (6), RP-6306, and WEE1 inhibitor AZD1775, with efficacy correlating to improved WEE1 activity. Compound 24 also showed favorable in vitro ADME and early safety profiles, supporting dual checkpoint targeting in checkpoint-deficient cancers.

These findings reveal a novel cytoplasmic function of WEE1 in sustaining MYC stability and chemoresistance. Targeting WEE1 destabilizes MYC and enhances therapeutic response, supporting the combination of MK-1775 and Panobinostat as a promising treatment strategy for EAC.

P2, N=124, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2026 --> Mar 2027

P2, N=273, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Sep 2026

P1, N=56, Completed, AstraZeneca | Active, not recruiting --> Completed

In this study, we developed long-term resistant (lt-res, several months) pre-clinical models of two drugs inducing mitotic arrest in TP53-mutated cells: adavosertib (ADA), an investigational WEE1 inhibitor targeting the DNA damage response and currently evaluated in clinical trials, and paclitaxel (PTX), a widely used chemotherapeutic agent in cancer care targeting microtubules. Notably, upregulation of receptor tyrosine kinases, such as ROR1, was observed in both ADA and PTX lt-res models with activated PI3K/AKT signaling. Targeting ROR1 with zilovertamab-vedotin, a monoclonal antibody-drug conjugate, resulted in enhanced cytotoxicity, demonstrating a new approach against recurrent drug-resistant ovarian cancer.

The combination of WEE1 inhibitor adavosertib and vinca alkaloid vincristine demonstrated the highest activity, which was validated in TP53mut SHH-MB patient-derived organoids. Despite the drugs' limited efficacy in the in vivo PDX model, WEE1 knockdown led to significant growth reduction in in vitro and in vivo TP53mut SHH-MB models. Our findings identify WEE1 as a promising target in LFS SHH-MB, suggesting its inhibition combined with vincristine treatment as a potential chemotherapeutic strategy.

Elevated expression of CPSF73 is associated with aggressive disease in prostate cancer patients, and combining JTE-607 with adavosertib synergistically reduced prostate cancer cell survival. Our findings suggest that transcription termination helps prevent toxic conflicts between transcription and replication following increased replication initiation caused by WEE1 inhibition.

P2, N=96, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=49, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2026 --> Jul 2027 | Trial primary completion date: Dec 2025 --> Jul 2026

We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.

PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may therefore have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC.