THERAPEUTIC STRATEGY TO KILL CANCER CELL

Inhibiting two distinct repressors of p53 can elicit cancer cell death through activation of a complementary gene network

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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, pushing the gas pedal all the way to the floor, whereas mutations in tumour suppressor genes can cause tumours to grow unchecked--a situation in which there are no brakes. Researchers studying mutations in tumor suppressor genes have dedicated significant focus to p53, the most frequently mutated tumor suppressor gene in human cancers. Over the past two decades, much effort has been devoted to designing biologically targeted therapies that specifically activate p53. However, while research has shown that these therapies are effective at inducing p53 activity, they generally can’t kill cancer cells. As observed for other biologically targeted therapies, activation of p53 has been shown to stop tumor growth for a period of time, but the cells eventually mutate and become resistant to treatment. 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. When you block both the major p53 repressor, known as MDM2, and its minor repressor, known as PPMID, p53 works much better in terms of induc-