Abstract
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.
Original language | English (US) |
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Pages (from-to) | 479-494 |
Number of pages | 16 |
Journal | Cancer cell |
Volume | 26 |
Issue number | 4 |
DOIs | |
State | Published - Oct 13 2014 |
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
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