LKB1 is a DNA damage response protein that regulates cellular sensitivity to PARP inhibitors

Abstract

Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), γ-H2AX, and breast cancer susceptibility 1 (BRCA1). ATM mediated LKB1 phosphorylation at Thr 363 following the exposure of cells to ionizing radiation (IR). LKB1 interacted with BRCA1, a downstream effector in DDR that is recruited to sites of DNA damage and functions directly in homologous recombination (HR) DNA repair. LKB1 deficient cells exhibited delayed DNA repair due to insufficient HR. Notably, LKB1 deficiency sensitized cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Thus, we have demonstrated a novel function of LKB1 in DNA damage response. Cancer cells lacking LKB1 are more susceptible to DNA damage-based therapy and, in particular, to drugs that further impair DNA repair, such as PARP inhibitors.

WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non–Small Cell Lung Cancer

“…We sought to take advantage of LKB1 deficiency in the context of DNA damage/repair, and our data suggest that patient tumors harboring mutant KRAS with loss of LKB1 may respond more effectively to WEE1 inhibition, either alone or in combination with DNA-damaging therapies. Recent work by Wang and colleagues (34) demonstrated that LKB1-deficient cells were more sensitive to PARP inhibitors, and that LKB1 could interact with ATM and BRCA1 as part of the DNA damage response pathway. Our data also suggest that T366, a phosphorylation site for ATM on LKB1 is necessary for the resistance conferred by wild-type LKB1 to AZD1775 exposure.…”

STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation

“…Together, these functions contribute to the induction of epithelial mesenchymal transition (EMT) and metastasis 27 , 28 . In addition to this, in vivo experiments have shown evidence for the contribution of LKB1 to genotoxic DNA damage response and DNA damage repair 12 , 29 .…”

The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer

“…As mentioned above mutations in STK11/LKB1 and consequential disruption of AMPK signaling pathways are amongst the most frequent aberrations in lung cancers [reviewed in (94)]. Both LKB1 and AMPK have been suggested to have roles in DNA repair pathways, however the full extent of the influence of LKB1 downregulation on DNA repair pathways in lung cancer has not yet been explored (95,96).…”