TY - JOUR
T1 - Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors
AU - Cheung, Lydia W.T.
AU - Yu, Shuangxing
AU - Zhang, Dong
AU - Li, Jie
AU - Ng, Patrick K.S.
AU - Panupinthu, Nattapon
AU - Mitra, Shreya
AU - Ju, Zhenlin
AU - Yu, Qinghua
AU - Liang, Han
AU - Hawke, David H.
AU - Lu, Yiling
AU - Broaddus, Russell R.
AU - Mills, Gordon B.
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/10/13
Y1 - 2014/10/13
N2 - 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 PIK3R1L370fs unexpectedly 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.
AB - 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 PIK3R1L370fs unexpectedly 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84907967403&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2014.08.017
DO - 10.1016/j.ccell.2014.08.017
M3 - Article
C2 - 25284480
AN - SCOPUS:84907967403
SN - 1535-6108
VL - 26
SP - 479
EP - 494
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -