Dual Activation of p53 and Integrated Stress Response Kills Cancer Cells

Gene mutations are the cause of cancer. Tumor suppressors and oncogenes are the two main groups of these altered genes in cancer. Mutations in oncogenes can drive cell proliferation, whereas mutations in tumour suppressor genes can cause tumours to grow unchecked. Researchers studying mutations in tumor suppressor genes have dedicated significant focus to p53, the most frequently mutated tumor suppressor gene in human cancers. While research has shown that therapies are effective at inducing p53 activity, they generally can’t kill cancer cells. New research by University of Colorado Cancer Center scientists illuminates the mechanisms at work that prevent p53 activation from triggering effective cancer cell death. They show that inhibiting two distinct repressors of p53 can elicit cancer cell death through activation of a complementary gene network known as the Integrated Stress Response. Researchers have repurposed the drug Nelfinavir, which originally was approved as an HIV therapy, to activate the Integrated Stress Response. Research is continuing to understand more about mechanisms of the synergistic response that happens when MDM2 and PPM1D are inhibited and p53 is activated.