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Updated: Feb 28, 2026

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

Juuli Raivola1, Frida Rantanen2, Alice Dini2

  • 1Applied Tumor Genomics, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.

Cell Death & Disease
|February 26, 2026
PubMed

Insights

Drug resistance in ovarian cancer is a major hurdle. Researchers identified a shared signaling pathway that allows cancer cells to adapt to chemotherapy, offering new therapeutic targets like ROR1 for improved treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Drug resistance is a significant challenge in treating ovarian cancer, a leading cause of cancer-related death in women.
  • Developing effective, long-term treatment strategies for recurrent ovarian cancer requires understanding the mechanisms of drug resistance.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying long-term drug resistance to mitotic inhibitors in TP53-mutated ovarian cancer.
  • To identify shared adaptive signaling pathways that confer resistance to adavosertib (ADA) and paclitaxel (PTX).

Main Methods:

  • Development of long-term resistant (lt-res) pre-clinical ovarian cancer models.
  • Integrated multi-omics functional profiling to analyze adaptive signaling.
  • Evaluation of ROR1 targeting with zilovertamab-vedotin in resistant models.

Main Results:

  • A shared PI3K/AKT-regulated signaling node was identified, governing adaptation to both ADA and PTX.
  • This node modulates DNA damage responses, enabling cells to adopt either a proliferative
  • fast-bypass
  • or a
  • slow-repair
  • state.
  • Upregulation of receptor tyrosine kinases, including ROR1, was observed in resistant models with activated PI3K/AKT signaling.

Conclusions:

  • The PI3K/AKT pathway plays a critical role in mediating adaptive resistance to mitotic inhibitors in ovarian cancer.
  • Targeting ROR1, a receptor tyrosine kinase upregulated in resistant cells, with antibody-drug conjugates like zilovertamab-vedotin shows promise for overcoming drug resistance.

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