Small Molecule Inhibition of PDE6D-RAS Interaction Suppresses the Growth of Acute Lymphoblastic Leukemia Cell Lines

The activation of RAS signaling has been shown to act as the driver of both de novo and relapsed, chemotherapy resistant acute lymphoblastic leukemia (ALL). Full RAS transformation requires the activity of the small RAS-related C3 botulinum toxin substrate (RAC) protein family, including the hematopoietic-specific RAC2 GTPase and we have previously demonstrated the role of RAC in specific leukemia types. Even though relapsed ALL patients have a 34% overall prevalence of RAS-activating mutations, KRASG12C mutations were not present, suggesting that the only RAS inhibitor currently available (G12C-specific) would not be effective in treating these patients. Phosphodiester 6 subunit delta (PDE6D), initially identified as a subunit of rod-specific photoreceptor phosphodiesterase, is now also known as a transporter of prenylated cargo. In fact, PDE6D has been shown to modulate the activity of RAS family proteins by regulating their subcellular location. When active, RAS proteins migrate to the cell membrane where they interact with a number of effectors triggering pro-survival downstream pathways including the mitogen-activated protein kinase / extracellular signaling-regulated kinase (MAPK/ERK) and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT). MAPK/ERK and PI3K/AKT pathways in particular are believed to synergize to induce survival and cellular transformation.