Reuben Shaw – Distinguished Lecture Series

Decoding critical targets of the LKB1/STK11 Tumor Suppressor Kinase in NSCLC

Reuben Shaw, PhD

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ABSTRACT:

Inactivating 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 members of the AMP-activated protein kinase family. The function of many of the AMPK-related kinases (AMPKRs) remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Recently we have combined CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing multiple surprises. First, despite an unwavering role in inhibiting mTOR pro-growth signaling, loss of AMPK at initiation in Kras GEMMs results in a block in tumor progression, which we could connect to a loss of lysosome and metabolic adaptive capability. Moreover, we found a surprisingly critical role for the SIK subfamily. Conditional genetic loss of Sik1 revealed increased tumor growth in mouse models of Kras – dependent lung cancer, which was further enhanced by loss of the related kinase Sik3. As most known direct substrates of SIK1 and SIK3 control transcription, gene-expression analysis was performed, revealing specific transcriptional programs that contribute to LKB1-dependent tumorigenesis. Additional pathways by which one might therapeutically target these tumors based on the signaling and metabolic pathways dysregulated from LKB1-deficiency will be discussed.

View the University of Illinois Cancer Center Distinguished Lecture Series schedule here.