Exploitation of KAT6A for the treatment of PPP2R1A-mutated cancers

PPP2R1A, encoding a subunit of the protein phosphatase 2A (PP2A) enzyme, is mutated in >1% of cases across diverse human cancer types 1. Notably, PPP2R1A mutations are often observed in gynecological cancers 1. To date, clinically applicable therapy based on PPP2R1A mutational status with a durable outcome has not been described. Here we show that inhibition of the KAT6A acetyltransferase induces senescence of PPP2R1A-mutated cancer cells and that PPP2R1A mutational status correlated with response to the KAT6A inhibitors. Mechanistically, mutant PPP2R1A creates KAT6A dependence by regulating transcription of the ubiquitin E3 ligase SKP2 to suppress senescence via degrading p27. Notably, KAT6A inhibition in combination with senolytics such as ABT263 that trigger apoptosis of senescent cells regressed PPP2R1A-mutated tumors. In addition, KAT6A inhibition synergized with immune checkpoint blockade to eradicate PPP2R1A-mutated tumors in vivo. Our data indicate that pharmacological inhibition of KAT6A alone or in combination with senolytics or immune checkpoint blockades represents effective therapeutic strategies for cancers involving PPP2R1A mutations.