Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC.
Multivariate analysis indicated that adenocarcinoma (P<0.05), lymph node metastasis (P<0.05), advanced TNM stage (P<0.001) and reduced expression of LKB1 (P<0.05) and Beclin1 (P<0.001) are all independent prognostic indicators for the survival of NSCLC patients.
Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug.<b>Conclusions:</b> Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab.<i></i>.
Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy.
LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small cell lung carcinoma (NSCLC)-like).
In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC.
In the case of LCNECs, which present with a high mutation burden, two major molecular subtypes have been identified: one with biallelic inactivation of tumor protein p53 gene (TP53) and retinoblastoma gene (RB1), a hallmark of SCLC; and the other one with biallelic inactivation of TP53 and serine/threonine kinase 11 gene (STK11)/kelch like ECH associated protein 1 gene (KEAP1), genes that are frequently mutated in NSCLC.
Hence, our findings support that enhanced E-cadherin by GA cooperates LKB1, leading to up-regulation of p-AMPK, and thus blocking of mTOR signaling pathway, which provide theoretical foundation for utilization of GA as a potential targeted drug against NSCLC harboring wild-type LKB1.
Data from several independent groups have provided information about the profiles of lung tumors with LKB1 inactivation and it is generally agreed that this alteration strongly predominates in non-small cell lung cancer, in particular adenocarcinomas, in smokers.
Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC.