Within the intricate landscape of cell membrane lipids and the kinase enzymes that regulate them, phosphoinositide 3-kinases (PI3Ks) have long dominated scientific research, particularly due to their roles in cancer, diabetes, and various cellular functions. However, the spotlight on PI3Ks has often overshadowed other crucial members of this lipid enzyme family, including phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks).
Brooke Emerling, Ph.D., co-director and associate professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys, is leading a resurgence of interest in these underexplored enzymes. Emerling and her team have made a groundbreaking discovery connecting PI5P4K activity to the regulation of the hippo pathway—an ancient signaling system instrumental in organ growth and size control, conserved across diverse species. This study, published in Science Signaling, offers promising new research avenues for tackling aggressive cancers.
“Up till now, my lab has focused on what these enzymes are, why PI5P4Ks are important, and how they affect tumor growth,” says Emerling. “Given the potential to target these enzymes with new drugs to treat cancer, it is crucial to understand their functions and regulatory mechanisms.”
To expand the understanding of PI5P4K regulators, the research team screened 29 potential candidates and identified two—MST1 and MST2, core components of the hippo pathway—that effectively inhibited PI5P4K activity.
“These results are exciting because the hippo pathway is a major pathway dysregulated in cancer,” notes Emerling. “Developing drugs that directly target the hippo pathway has been challenging, so discovering a link to PI5P4Ks opens up a potential new therapeutic strategy for cancers with abnormal hippo signaling.”
Further experiments with genetically engineered cells showed elevated PI5P4K activity in the absence of MST1 and MST2, indicating that these kinases might regulate PI5P4K. “Our hypothesis is that MST1 and MST2 keep PI5P4Ks in check,” says Emerling. “When MST activity is lost in cancer cells, PI5P4K remains active, contributing to aggressive metastatic tumors.”
The team also investigated how PI5P4K activity influences other components of the hippo pathway, finding that reduced PI5P4K activity correlated with decreased activity of the Yes-associated protein (YAP), a key player at the pathway's end that is directly linked to cancer.
“YAP is often used as a biomarker for aggressive tumors and is easy to stain in patient biopsies,” says Emerling. “Researchers have been attempting to develop drugs targeting YAP, but our findings suggest inhibiting PI5P4K might be a more viable strategy. Several PI5P4K inhibitors have already been developed, and we can explore their potential in future cancer treatments.”
Building on these findings, the research team plans to delve deeper into the molecular interactions at the intersection of PI5P4K and the hippo pathways through structural biology. Preclinical studies will also be conducted to test PI5P4K inhibitors in mouse tumor models, measuring effects on YAP activity and evaluating potential benefits for cancer patients.
This study extends Emerling's prior work published in Science Advances, which demonstrated that targeting PI5P4Kα could kill prostate cancer cells. “This research has significant potential to improve patient outcomes, and we're committed to advancing these discoveries,” adds Emerling.
Collaborators on this study include Lavinia Palamiuc, Ryan M. Loughran, Gurpreet K. Arora, Vivian Tieu, Kyanh Ly, Alicia Llorente, Sophia Crabtree, Archna Ravi, and Rabi Murad from Sanford Burnham Prebys; Jared L. Johnson and Jenny C. Y. Wong from Weill Cornell Medicine; Zeinab Haratipour and Woong Jae Choi from Vanderbilt University Medical Center; and Thorsten Wiederhold from Cell Signaling Technology, Inc.
Source: Sanford-Burnham Prebys