LKB1 suppresses growth and promotes the internalization of EGFR through the PIKFYVE lipid kinase

The tumor suppressor LKB1 is a serine/threonine protein kinase that is frequently mutated in human lung adenocarcinoma (LUAD). LKB1 regulates a complex signaling network that is known to control cell polarity and metabolism; however, the pathways that mediate the tumor suppressive activity of LKB1 are incompletely defined. To identify mechanisms of LKB1- mediated growth suppression we developed a spheroid-based cell culture assay to study LKB1- dependent growth. Using this assay, along with genome-wide CRISPR screens and validation with orthogonal methods, we discovered that LKB1 suppresses growth, in part, by activating the PIKFYVE lipid kinase, which promotes the internalization of wild-type EGFR. Our findings reveal a new mechanism of regulation of EGFR, which may have implications for the treatment of LKB1 -mutant LUAD. ### Competing Interest Statement H.V. is a member of the scientific advisory boards (SABs) for Dragonfly Therapeutics and Surrozen. N.E.S. is an advisor of Vertex and Qiagen and is a co-founder and advisor of OverT Bio. L.C.C. is a co-founder of Faeth Therapeutics, Volastra Therapeutics, and Larkspur Biosciences and is a member of their SABs. L.C.C. is also a co-founder of Agios Pharmaceuticals and is a former member of its SAB and board of directors. M.M. is employed by and holds stock in 23andMe, Inc. All other authors declare no potential conflicts of interest.