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.
CITATION STYLE
Cheung, L. W. T., Yu, S., Zhang, D., Li, J., Ng, P. K. S., Panupinthu, N., … Mills, G. B. (2014). Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell, 26(4), 479–494. https://doi.org/10.1016/j.ccell.2014.08.017
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