Major finding: Tumor-associated PIK3R1 truncation mutations promote activation of ERK and JNK signaling.
Mechanism: Nuclear PIK3R1R348* facilitates JNK protein complex assembly and induces prosurvival signaling.
Impact: Gain-of-function PIK3R1 mutations may represent a functional therapeutic target in cancer.
Mutations in PIK3R1, which encodes the p85α regulatory subunit of PI3K, are one of the most frequent genetic alterations observed in cancer. Interestingly, the most common recurrent PIK3R1 mutation, the PIK3R1R348* truncation mutation, does not activate the p110α catalytic PI3K subunit, as is observed with other PIK3R1 mutations, but instead has been shown to possess a gain-of-function activity. Neomorphic PI3KR1 mutations have broad implications for therapeutic treatment strategies, prompting Cheung and colleagues to study the functional consequences of PIK3R1R348* on cell survival, signaling, and drug sensitivity. A cytotoxicity screen using a collection of 145 compounds in cells expressing wild-type PIK3R1, PIK3R1R348*, or the PTEN-destabilizing mutant PIK3R1E160* revealed that distinct PIK3R1 mutations differentially sensitized cells to PI3K pathway inhibitors. Surprisingly, PIK3R1R348* expression rendered cells sensitive to MAPK pathway inhibitors, in particular MEK and JNK kinase inhibitors. In line with these results, an ovarian endometrioid cancer cell line harboring the neighboring PIK3R1L370fs truncation mutation also displayed sensitivity to MEK and JNK inhibition. Mechanistically, PIK3R1R348*-expressing and PIK3R1L370fs-expressing cells were characterized by elevated nuclear ERK1/2 and JNK phosphorylation, which was dependent on mutant PIK3R1 expression but occurred independently of canonical PI3K–AKT signaling. Dissection of these pathways revealed that PIK3R1R348* promoted ERK phosphorylation via BRAF-mediated activation of the MAPK kinases MKK1 (also known as MAP2K1) and MKK2 (MAP2K2), whereas PIK3R1R348*-driven activation of the JNK pathway was dependent on nuclear localization and phosphorylation of MLK3 (MAP3K11) and MKK7 (MAP2K7). PIK3R1R348* functioned as a scaffold to stabilize a multiprotein complex containing the small GTPases CDC42 and RAC1, MLK3, MKK7, JNK1, and JNK2 in the nucleus and activated JNK signaling to promote cell survival and invasion both in vitro and in vivo. Together, these findings highlight the functional contribution of neomorphic PIK3R1 mutations to cancer cell growth and provide insight into therapeutic strategies to target PIK3R1R348*-mutant tumors.
- ©2014 American Association for Cancer Research.
Volume 4, Issue 12
