Novel Facts About FAK: New Connections to Drug Resistance?
Menée sur des lignées cellulaires de cancer ovarien résistant aux taxanes et 105 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer de l'ovaire, cette étude met en évidence des mécanismes associés à l'activité antitumorale d'un composé appelé VS-6063, un inhibiteur de la kinase d'adhérence focale
Resistance to taxane chemotherapy presents a major hurdle in the treatment of recurrent ovarian cancer. The majority of epithelial ovarian cancers are sensitive to paclitaxel or docetaxel with initial treatment, but resistance ultimately develops in the majority of women. Development of a successful method to maintain susceptibility to taxane and platinum chemotherapy is an unmet clinical need. The article by Kang and colleagues in the current issue of the Journal describes a novel mechanism of taxane resistance, through FAK-dependent upregulation of YB-1, a transcription factor that in turn upregulates CD44 (1). Intriguing findings in their work include the importance of nuclear-activated p397Tyr-FAK for this resistance process, and the demonstration that nuclear colocalization of activated FAK and p102Ser-YB1 dichotomized overall survival of patients with ovarian cancer.
How might this relate to taxane resistance in ovarian cancer? The mechanism of anticancer activity of taxanes relies on their ability to bind and stabilize polymerized tubulin. Stabilization of tubulin filaments prevents spindle disassembly during mitosis, leading to catastrophic cell death. Lack of tubulin depolymerization also prevents transport of proteins within nondividing cells, a likely cause for neuropathy associated with taxane therapy. Additionally, the decrease in free tubulin leads to mitochondrial hyperpolarization and release of cytochrome …
Journal of the National Cancer Institute , éditorial en libre accès, 2013