Ovarian Cancer Cells Develop Resistance to Chemotherapy through a Complex Signaling Pathway

Strategic Insights -

Research conducted in Hong Kong, People's Republic of China, has uncovered a molecular mechanism by which ovarian cancer cells develop resistance to chemotherapy. The study found that ovarian cancer cells grown in three-dimensional cultures resisted apoptosis (programmed cell death) and chemotherapy-induced cell death, despite being exposed to clinically relevant doses of two front-line chemotherapeutic drugs, cisplatin and paclitaxel.

Key Takeaways:

  • Ovarian cancer cells developed a remarkable resistance to anoikis (apoptosis induced by cell detachment) and chemotherapy-induced cell death when grown in three-dimensional cultures.
  • Inhibition of the HGF receptor c-Met, which is frequently overexpressed in ovarian cancer, restored chemosensitivity in three-dimensional cultures.
  • The acquired anoikis resistance was dependent on both phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) 1/2 signaling pathways.
  • Inhibitors of PI3K/Akt abrogated ERK1/2 activation and its associated anoikis resistance in response to HGF, suggesting a signaling relay between these two pathways.
  • Researcher M.K. Tang and colleagues identified a central role of Ras as a mechanism of this cross-talk, where Ras did not lie upstream of PI3K/Akt, but PI3K/Akt signaling involved Ras.
  • The study's findings may have important clinical implications for understanding the apoptotic resistance mechanism of nonadherent ovarian cancer ascites cells.

Statistics:

  • 70-80% of ovarian cancer patients develop chemoresistance, leading to treatment failure and poor prognosis.
  • Ovarian cancer is the most lethal gynecologic cancer, with widespread peritoneal dissemination and malignant ascites.
  • The HGF receptor c-Met was found to be overexpressed in 70-80% of ovarian cancer cases.
  • The study used a nonadherent cell culture model to investigate the molecular mechanisms of apoptotic resistance of ovarian cancer cells.

Sources:

  • Tang, M.K., et al. "c-Met overexpression contributes to the acquired apoptotic resistance of nonadherent ovarian cancer cells through a cross talk mediated by phosphatidylinositol 3-kinase and extracellular signal-regulated kinase 1/2." Neoplasia, 2010;12(2):128-38.