Genome editing of LKB1 (STK11) mutation in A549 lung cancer cells using CRISPR/Cas9 system

Resumo

Mutations and deletions of the tumor suppressor LKB1 (STK11) are common in several malignancies, especially in non-small lung cancer cells (NSCLC). In that cell type, LKB1 inactivation coexists with mutations at other important cancer genes, including KRAS and TP53. The mutant LKB1 indirectly increases transcription of genes involved in metastasis, including COX-2. LKB1 directly activates AMPK decreasing mTOR activity and plays roles in several other processes such as cell metabolism, cell polarity, apoptosis and DNA damage via p53 interaction. Metformin, an antidiabetic drug, have shown antitumor effects, sensitizes cells in coadjuvant cisplatin treatment and acts in AMPK independent and dependent mechanisms. Thus, we propose the application of CRISPR/Cas9 system as genome editing tool to correct the LKB1 nonsense mutation and restore protein expression, providing new insights regarding cisplatin resistance, survival and metformin response in A549 lung cancer cells.