Restoring tumor suppression

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Science  17 May 2019:
Vol. 364, Issue 6441, pp. 633-634
DOI: 10.1126/science.aax5526

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Many oncogenes and tumor suppressors that are mutated during cancer development act as enzymatic switches that phosphorylate (kinases) or dephosphorylate (phosphatases) substrates. Much attention has focused on therapeutically inhibiting oncogenic kinases that are activated by mutation. However, there has been less focus on targeting phosphatases, despite their importance in cancer development. The tumor suppressor PTEN (phosphatase and tensin homolog on chromosome 10) is the most frequently inactivated phosphatase in human cancer (1, 2). The loss of PTEN phosphatase activity increases downstream activity of the phosphatidylinositol 3-kinase (PI3K)–AKT signaling pathway (3, 4). Preclinical studies have shown that targeting the PI3K-AKT pathway reduces tumor growth when PTEN is inactivated (5). However, many PTEN mutant tumors are resistant to such therapies. On page 651 of this issue, Lee et al. (6) activate PTEN phosphatase by inhibiting a newly described inhibitory system and thereby reduce PI3K-AKT signaling and tumor growth in mice.