A SIAH of K-RAS relief
Researchers at the Mayo Clinic College of Medicine have shown that inhibiting the activity of an E3 ubiquitin ligase can inhibit cell proliferation and increase apoptosis across various types of lung and pancreatic cancers.1 The most dramatic effects were in aggressive cancer cell lines driven by activating RAS mutations, which tend to be resistant to marketed drugs and radiotherapy. Targeting the ligase in vivo will be challenging, however.
The target, seven in absentia homolog 2 (SIAH2), is a downstream component in the mammalian RAS signaling pathway and is upregulated in cancer cells compared with in normal cells. Previous work had suggested that SIAH2 has substrates that can affect more upstream components like v-raf-1 murine leukemia (RAF) and mitogen-activated protein kinases (MAPKs) through negative-feedback regulation.2,3...