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.