Naturally Occurring Neomorphic PIK3R1 Mutations Activate the MAPK Pathway, Dictating Therapeutic Response to MAPK Pathway Inhibitors
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation MAPK, deux mutations d'une sous-unité de PI3K confèrent aux cellules cancéreuses une sensibilité aux inhibiteurs de MEK et JNK
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 in vitro and in vivo. 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.