UC San Diego

Mutations in the Kirsten ras oncogene homolog from the mammalian ras gene family (KRAS) are often observed in patients suffering from several forms of cancers. These activating mutations in KRAS are suggested to be implicated in approximately 30% of non-small cell lung cancers (NSCLC). Among these patients with activating KRAS mutations, the most prevalent co-mutation occurs with the tumor suppressor serine/threonine kinase 11 (STK11), also known as Liver kinase B1 (LKB1). Co-mutations in KRAS and LKB1 make the tumors hyperaggressive and modulates the sensitivity to various therapeutics. The function of LKB1 in vivo is diverse, and is central to cellular metabolism, polarity, and growth. LKB1 phosphorylates and activates 14 downstream kinases known as the AMPK-related kinases (AMPKRs), which upon several known and unknown stimuli, control these above-mentioned cellular processes. While several seminal findings have been made regarding KRAS-LKB1 (KL) driven NSCLC, one of the most significant findings showed loss of the salt-inducible kinase family (SIKs), specifically SIK1 and SIK3, enhanced KRAS driven tumor growth, and approached that of the loss of LKB1. Here we show how loss of all three Sik family members in Kras-driven (KS) genetically engineered murine models of NSCLC leads to enhanced tumorigenesis, and most closely resembles the KL tumor growth phenotype. We further characterize distinct biological overlaps between KL and KS tumors, to show to what extend the Sik’s mediate Lkb1-dependent tumor biology and tumor suppression. Transcriptional analysis of these tumors revealed expression differences in several well characterized pathways, which changed in common in both KL and KS tumors. Ultimately we aimed to target several enriched pathways or individual genetic targets using an in vivo Cas9 screen, in order to uncover LKB1/SIK dependencies that can serve as future potential therapeutic or pharmacological targets for patients suffering from LKB1 mutations in NSLCLC.