The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non–Small Cell Lung Cancer

Abstract

Introduction: Liver kinase B1 (LKB1), also called serine/ threonine kinase 11 (STK11), is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Approximately 30% to 35% of patients with NSCLC possess inactivated liver kinase B1 gene (LKB1), and these patients respond poorly to antiprogrammed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy. Therefore, novel therapies targeting NSCLC with LKB1 loss are needed. Methods: We used a new in silico signaling analysis method to identify the potential therapeutic targets and reposition drugs by integrating gene expression data with the Kyoto Encyclopedia of Genes and Genomes signaling pathways. LKB1 wild-type and LKB1-deficient NSCLC cell lines, including knockout clones generated by clustered regularly interspaced short pallindromic repeats-Cas9, were treated with inhibitors of mechanistic target of rapamycin kinase (mTOR) and phosphatidylinositol-4,5-bisphosphate 3kinase (PI3K) and a dual inhibitor. Results: In silico experiments showed that inhibition of both mTOR and PI3K can be synergistically effective in LKB1-deficient NSCLC. In vitro and in vivo experiments showed the synergistic effect of mTOR inhibition and PI3K inhibition in LKB1-mutant NSCLC cell lines. The sensitivity to dual inhibition of mTOR and PI3K is higher in LKB1mutant cell lines than in wild-type cell lines. A higher compensatory increase in Akt phosphorylation after rapamycin treatment of LKB1-deficient cells than after rapamycin treatment of LKB1 wild-type cells is responsible for the synergistic effect of mTOR and PI3K inhibition. Dual inhibition of mTOR and PI3K resulted in a greater decrease in protein expression of cell cycle-regulating proteins in LKB1 knockout cells than in LKB1 wild-type cells. Conclusion: Dual molecular targeted therapy for mTOR and PI3K may be a promising therapeutic strategy in the specific population of patients with lung cancer with LKB1 loss.

LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors

“…A recently published paper shows that the dual inhibition of mTOR and PI3K can be a promising therapeutic strategy for LKB1-deficient tumors. 30 These data are in line with our results where we inhibited the PI3K and mTOR target S6 through the inhibition of ERK/p90RSK/S6 axis.…”

MicroRNA‑106a‑5p promotes the proliferation, autophagy and migration of lung adenocarcinoma cells by targeting LKB1/AMPK

“…Overall, ~30% of patients with NSCLC are reported to have mutations in LKB1 worldwide (52). LKB1 mutations can cause abnormal phosphorylation of the PI3K/mTOR pathway, and participate in the progression of lung cancer (53). Han et al (54) revealed that LKB1 inhibited the proliferation of periosteal mesenchymal progenitors and xenograft tumors by inhibiting mTOR phosphorylation, and demonstrated that the LKB1-mTORC1 pathway may be a target for treating osteogenic tumors.…”

Rapamycin and trametinib: a rational combination for treatment of NSCLC

“…It forms two distinct complexes, called mTOR complex 1 (mTORC1) and mTORC2, of which only mTORC1 is sensitive to the macrolide rapamycin [30][31][32]. Specifically, mTORC1 can phosphorylate ribosomal protein S6 kinase (S6K) and eIF4E binding protein 1 (4EBP1) to increase translation of mRNAs, while mTORC2 controls cell survival via activation AKT and SGK1 pathway [33,34]. Initial studies mainly focus on inhibition of mTORC1 with rapamycin.…”