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