Lydia W.T. CheungShuangxing YuDong ZhangJie LiPatrick K.S. NgNattapon PanupinthuShreya MitraZhenlin JuQinghua YuHan LiangDavid H. HawkeYiling LuRussell R. BroaddusGordon B. MillsUniversity of Texas MD Anderson Cancer CenterMahidol University2018-11-092018-11-092014-01-01Cancer Cell. Vol.26, No.4 (2014), 479-49418783686153561082-s2.0-84907967403https://repository.li.mahidol.ac.th/handle/20.500.14594/33348© 2014 Elsevier Inc. PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1R348*and a nearby mutation PIK3R1L370fs, in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors invitro and invivo. Consistent with the response to inhibitors, PIK3R1R348*and PIK3R1L370fsunexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348*and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1R348*and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.1016/j.ccell.2014.08.017