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Title: Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors
Authors: Lydia W.T. Cheung
Shuangxing Yu
Dong Zhang
Jie Li
Patrick K.S. Ng
Nattapon Panupinthu
Shreya Mitra
Zhenlin Ju
Qinghua Yu
Han Liang
David H. Hawke
Yiling Lu
Russell R. Broaddus
Gordon B. Mills
University of Texas MD Anderson Cancer Center
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Jan-2014
Citation: Cancer Cell. Vol.26, No.4 (2014), 479-494
Abstract: © 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.
ISSN: 18783686
Appears in Collections:Scopus 2011-2015

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