The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

Abstract

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the <i>PTEN</i> and <i>TP53</i> tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of <i>Pten/Trp53</i> mutant metastatic prostate cancer, we found that complete loss of <i>Phlpp2</i> paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill <i>PTEN</i> mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.