The AMPK-related kinases SIK1 and SIK3 mediate key tumor suppressive effects of LKB1 in NSCLC

Mutations in the LKB1 (STK11) tumor suppressor are the third most frequent genetic alteration in non-small-cell lung cancer (NSCLC). LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases ("AMPKRs"). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor suppressive function of LKB1 remains unknown. Here we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of Sik1 revealed increased tumor growth in mouse models of Kras-dependent lung cancer, which were further enhanced by loss of the related kinase Sik3. As most known substrates of the SIKs control transcription, gene expression analysis was performed, revealing upregulation of AP-1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as proliferation benefits from SIK-loss.