ROR1-PI3K/AKT signaling drives adaptive resistance to cell cycle blockade in TP53 mutated ovarian cancer
We developed long-term resistant (lt-res, several months) pre-clinical models to adavosertib (ADA) and paclitaxel (PTX). We identified distinct transcriptomic and morphological changes in the ovarian cancer lt-res models. ADA resistance involves signaling pathway alterations that allow cells to maintain unchecked proliferation, while PTX resistance primarily stems from structural changes within the cell, affecting microtubules and drug efflux. Upregulation of receptor tyrosine kinases, such as ROR1, was observed in both ROR1-positive ADA and PTX lt-res models. Targeting ROR1 with zilovertamab-vedotin, a monoclonal antibody-drug conjugate, resulted in enhanced cytotoxicity, demonstrating a new approach against recurrent drug-resistant ovarian cancer. Overall design: Single-cell RNA-sequencing profiling of untreated parental and short-term, intermediate-resistant and long-term resistant ovarian cancer cell lines. Resistant cell lines were established by gradual increase of PTX or ADA concentrations.