ROR1-PI3K/AKT signaling drives adaptive resistance to cell cycle blockade in TP53 mutated ovarian cancer

Rákkutatás · Ovarian cancer · TP53

Targeting ROR1 with zilovertamab‑vedotin, a monoclonal antibody‑drug conjugate, resulted in enhanced cytotoxicity, demonstrating a new approach against recurrent drug‑resistant ovarian cancer.

Drug resistance remains a major challenge to durable responses in ovarian cancer, the fifth leading cause of cancer‑related death among women. 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. Through integrated multi‑omics functional profiling, we identify a shared PI3K/AKT‑regulated signaling node that governs drug adaptation across all lt‑res models. This node modulates the activity of DNA‑damage responses and genotoxic stress to toggle between two adaptive states: activated PI3K/AKT driving a proliferative “fast‑bypass” program with sustained cell cycle progression and mitotic evasion, or reduced PI3K/AKT signaling initiating a “slow‑repair” state characterized by DNA damage checkpoint engagement, replication slowdown, and increased drug efflux. 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.

Bizonyítékszint: Feltételezés / hírjelzés. Nincs önálló tudományos bizonyíték.

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