PIP4K2A/2B inhibitor suppresses tumor growth in a xenograft model of NSCLC

The PIP4K family of lipid kinases phosphorylates the rare phospholipid PI(5)P at the 4-position, generating PI(4,5)P 2 inside the cell. Although the functions of PIP4K, as well as the intracellular pools of PI(5)P and PI(4,5)P 2 , remain incompletely understood, there are emerging interests in developing inhibitors to target these kinases since their genetic ablations have broad tumor-suppressive and other beneficial effects. Here, we report continued optimization of a previously discovered 2-amino-dihydropteridinone PIP4K2A/2B inhibitor and demonstrate, for the first time that pharmacological inhibition of PIP4K2A/2B suppresses solid tumor growth in vivo . The tumor-suppressive effect of the inhibitor appears to be non-tumor cell-autonomous and is likely mediated by components of the tumor microenvironment, including macrophages that commonly adopt alternatively activated states and support tumor growth. Our findings suggest a potential role for PIP4K activity in tumor-associated macrophages and provide a rationale for further exploring pharmacological targeting of these lipid kinases in cancer.