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Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.

Abstract：

:PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1(R348∗) and a nearby mutation PIK3R1(L370fs), in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors in vitro and in vivo. Consistent with the response to inhibitors, PIK3R1(R348∗) and PIK3R1(L370fs) 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 PIK3R1(R348∗) and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Cheung LW,Yu S,Zhang D,Li J,Ng PK,Panupinthu N,Mitra S,Ju Z,Yu Q,Liang H,Hawke DH,Lu Y,Broaddus RR,Mills GB

doi

10.1016/j.ccell.2014.08.017

subject

Has Abstract

pub_date

2014-10-13 00:00:00

pages

479-94

issue

4

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(14)00349-3

journal_volume

26

pub_type

杂志文章

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