Naveed Saleh, MD, MS, for MDLinx | August 14, 2019
The conditional genetic loss of salt-inducible kinase 1 (SIK1) may drive non-small cell lung cancer (NSCLC) tumor growth. This may be further increased by the related SIK3, and positions these two kinases as critical targets for tumor inhibition in NSCLC treatment, according to the results of a study published in Cancer Discovery.
“For the first time, we’ve found specific direct targets for LKB1 that prevent lung cancer and discovered—very unexpectedly—that inflammation plays a role in this tumor growth,” said senior author Reuben J. Shaw, PhD, professor, Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, and director, Salk Cancer Center, La Jolla, CA. “With this knowledge we can hopefully develop new treatments for this large fraction of lung cancer patients.”
Two decades ago, LKB1/STK11 was discovered to be the single gene responsible for Peutz-Jeghers syndrome, an autosomal-dominant inherited cancer disorder. Then, LKB1/STK11 was discovered to be the third most frequent genetic mutation in NSCLC.
Mutations in LKB1 are observed in 20% of patients with NSCLC and commonly coexist with activating KRAS mutations. LKB1 codes for a serine/threonine kinase (STK) that activates a family of 14 downstream kinases—including the AMP-activated protein kinase (AMPK)—which is understood to mediate cell metabolism, cell polarity, and growth.
SIK1, SIK2, and SIK3 are three redundant kinases among the 14 AMPK family kinases (AMPKRs) dependent on LKB1 for their kinase activity. However, their roles were poorly understood—particularly their functions in controlling the effects of LKB1 gene expression in lung cancer.
In the current study, Dr. Shaw and fellow researchers assessed members of the AMPKR family through a combination of cellular systems and genetically engineered mouse models, and discovered that the AMPKR kinases SIK1 and SIK3 cooperatively control important tumor suppressor functions of LKB1 in KRAS-driven lung cancer in mice. Specifically, the researchers used CRISPR technology plus genetic analysis to inactivate each suspected kinase individually and then in combinations.
Head-to-head comparison of the 14 LKB1-dependent AMPKRs in A549 cells uncovered a unique role for the SIKs in suppressing soft agar colony formation, as well as susceptibility to cell death in detached conditions. In two assays, combined SIK1/SIK2/SIK3 deletion resulted in a phenotype most akin to LKB1 loss, with no other AMPKR subfamilies giving rise to similar effects on soft agar colony formation or growth in detached conditions.
Concomitant loss of SIK1 and SIK3 in KRAS mutant tumors cooperatively hastened lung tumorigenesis, and promoted the ability of tumors to grow vs those observed by loss of LKB1. Additionally, the loss of SIK1/3 recapitulated the reported phenotype seen in LKB1 mutant tumors, thus denoting a significant accumulation of neutrophils in tumor areas.
“Discovering that of the 14 kinases it was SIK1 and SIK3 that were the most critical players is like discovering that the relatively unknown backup quarterback who almost never plays is actually one of the most important quarterbacks in the history of the sport,” said Dr. Shaw. “By attacking the problem of lung cancer from different angles, we have now defined a single direct route that underpins how the disease develops in many patients.”
LKB1 is known to play a general role in suppressing inflammation in cells. Therefore, the team was fascinated to discover that SIK1 and SIK3 were specifically inhibiting the cellular inflammation response in lung cancer cells. When LKB1 or SIK1 and SIK3 mutate in tumors, inflammation is heightened, driving tumor growth.
“Given that only a handful of substrates are known for SIK1 and SIK3, there is much to be learned mechanistically about their function in lung cancer, which may have broad implications for resistance to checkpoint inhibitors and the large fraction of NSCLC bearing LKB1 mutations for which there are currently no robust therapeutic strategies,” concluded the authors.