In a recent publication in Cancer Cell, CTD2 investigators discovered that a known cancer-associated gain-of-function alteration in phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) results in novel protein activity that confers sensitivity to mitogen-activated protein kinase (MAPK) inhibitors. The PIK3R1 gene encodes the p85α regulatory subunit of PIK3. Under normal conditions, p85α suppresses PIK3 mediated activation of downstream pathways that promote cell growth and survival. Researchers from the University of Texas MD Anderson Cancer Center discovered that the previously identified gain-of-function mutant PIK3R1R348* and the nearby mutant PIK3R1L370fs are neomorphic because they have unique cellular activities compared to the wild-type protein and other mutants.
BaF3 cells expressing PIK3R1R348* were screened against 145 known inhibitors and exhibited sensitivity to MAPK inhibitors. This sensitivity was similarly shown in the ovarian endometrioid cancer cell line OVK18 that naturally contains the mutation PIK3R1L370fs. In contrast, sensitivity to MAPK inhibitors was not found in cells expressing PIK3R1E160* or other gain-of-function mutants. Using reverse phase protein arrays and other biochemical assays to evaluate protein signaling activity, the authors determined p85α R348* and p85α L370fs activate the extracellular-signal regulated kinase (ERK) and c-Jun N terminal kinase (JNK) pathways. This activation was not exhibited by wild type p85α, p85α E160* or other mutants. Thus, PIK3R1R348* and PIK3R1L370fs are considered neomorphic.
Through protein interaction studies, the researchers found p85α R348* acted upstream of ERK and JNK by functioning as a scaffold that forms a stable complex with small GTPases and upstream MAPK signaling proteins. This protein complex formation leads to aberrant signaling. The discovery of this neomorphic activity suggests that different alterations in the same protein may result in different behavior. Therefore, each alteration must be considered independently when developing cancer drugs for precision medicine.