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Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors.
- Source :
-
Cancer cell [Cancer Cell] 2014 Oct 13; Vol. 26 (4), pp. 479-94. Date of Electronic Publication: 2014 Oct 02. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Cell Nucleus metabolism
Class Ia Phosphatidylinositol 3-Kinase
Enzyme Activation
Humans
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation
Protein Transport
MAP Kinase Signaling System drug effects
Mutation
Phosphatidylinositol 3-Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 26
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 25284480
- Full Text :
- https://doi.org/10.1016/j.ccell.2014.08.017