This week we profile a recent publication in Nature from the lab of Dr. Alex Toker (pictured, back row, far left) with first authors Drs. Christian Dibble (back row, third from left) and Samuel Barritt (back row, far right) at Beth Israel Deaconess Medical Center and Harvard Medical School.
Can you provide a brief overview of your lab’s current research focus?
This study was a collaboration between the laboratories of Dr. Christian C. Dibble and Dr. Alex Toker at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston. The Dibble lab is focused on understanding how cellular metabolism, in particular Coenzyme A metabolism, is controlled by the major growth signaling pathways that are recurrently mutated in cancer. The Toker lab has a long history of discoveries concerning the role of the PI3K-AKT signaling pathway in breast cancer and in developing novel therapeutic strategies for targeting AKT in cancer.
What is the significance of the findings in this publication?
These findings, for the first time, revealed a direct regulatory connection between one of the major regulators of growth and metabolism, the PI3K signaling pathway, and one of the most critical metabolic cofactors, Coenzyme A (CoA). This study also revealed a new endogenous suppressor of CoA synthesis, the metabolite phosphatase PANK4 which is regulated by PI3K-AKT signaling. CoA is required for multiple core metabolic processes including nutrient catabolism, the TCA cycle, lipid synthesis, glycan synthesis, heme synthesis, and histone acetylation. Therefore, the ability of PI3K signaling to control cellular CoA supplies allows coordination of several key metabolic pathways required for growth.
What are the next steps for this research?
PI3K is pathologically activated in the majority of human cancers and CoA synthesis is deficient in the syndrome pantothenate-kinase-associated neurodegeneration (PKAN). Future studies could assess the therapeutic potential of inhibiting PANK4 activity to increase CoA synthesis in patients with PKAN or selectively inhibiting CoA synthesis in PI3K-dependent cancers.
If you’d like to mention your funding sources, please list them.
This work was supported by the following grants: V Foundation V Scholar Grant V2019-009, NIH/NCI R00-CA194314 (to C.C.D.); NIH F31-CA254169-01 (to S.A.B.); NIH F31-CA213460 (to R.C.G.); NSF DGE1144152 (to E.C.L.); NIH R00-CA230384 (to B.D.H.); NIH/NCI Intramural Research Program, Center for Cancer Research, ZIA BC011488 (to J.L.M.); NIH P01-CA120964, NIH P30-CA006516, BIDMC Capital Equipment Fund (to J.M.A.); NIH R01-CA177910, NIH R35-CA253097, Ludwig Center at Harvard (to A.T.).