Phosphorylation of FADD by the kinase CK1α promotes KRASG12D-induced lung cancer.

Genomic amplification of the gene encoding and phosphorylation of the protein FADD (Fas-associated death domain) is associated with poor clinical outcome in lung cancer and in head and neck cancer. Activating mutations in the guanosine triphosphatase RAS promotes cell proliferation in various cancers. Increased abundance of phosphorylated FADD in patient-derived tumor samples predicts poor clinical outcome. Using immunohistochemistry analysis and in vivo imaging of conditional mouse models of KRASG12D-driven lung cancer, we found that the deletion of the gene encoding FADD suppressed tumor growth, reduced the proliferative index of cells, and decreased the activation of downstream effectors of the RAS-MAPK (mitogen-activated protein kinase) pathway that promote the cell cycle, including retinoblastoma (RB) and cyclin D1. In mouse embryonic fibroblasts, the induction of mitosis upon activation of KRAS required FADD and the phosphorylation of FADD by CK1 alpha (casein kinase 1 alpha). Deleting the gene encoding CK1 alpha in KRAS mutant mice abrogated the phosphorylation of FADD and suppressed lung cancer development. Phosphorylated FADD was most abundant during the G(2)/M phase of the cell cycle, andmass spectrometry revealed that phosphorylated FADDinteractedwith kinases thatmediate the G(2)/M transition, including PLK1 (Polo-like kinase 1), AURKA (Aurora kinase A), and BUB1 (budding uninhibited by benzimidazoles 1). This interactionwas decreased in cells treated with a CKI-7, a CK1 alpha inhibitor. Therefore, as the kinase that phosphorylates FADD downstream of RAS, CK1 alpha may be a therapeutic target for KRAS-driven lung cancer.