New targets that when inhibited in combination with the activation of p53 can lead to cancer cell death are reported this week in Nature Chemical Biology.
p53 is a tumor suppressor that regulates cellular response to various stresses and it is known that the activation of p53 can promote cell death. The activation of p53 in cancer cells often results in reversible growth arrest rather than death of the cells. However, the pathways that govern cellular response-growth arrest versus death-in response to p53 activation are not well understood.
Joaquin Espinosa and colleagues perform a genome-wide screen to identify genes that modify response to the activation of p53 in cells that undergo growth arrest compared to those that die. They identify several pathways that were previously not known to impact a cell’s response to p53, and demonstrate that inhibition of the protein kinases ATM and MET in combination with activation of p53 promotes cell death. As inhibitors for both of these kinases are available but were set aside as they were not effective alone, the authors recommend that these drugs could be revisited and tested in combination with agents such as Nutlin-3 that activate p53.