LKB1 inactivation generates a redox imbalance that promotes ADC-to-SCC transdifferentiation in NSCLC.
Major finding: LKB1 inactivation generates a redox imbalance that promotes ADC-to-SCC transdifferentiation in NSCLC.
Mechanism: Impaired pentose phosphate pathway and fatty acid oxidation signaling leads to increased ROS.
Impact: Tumor plasticity may underlie resistance to ROS-inducing therapies in LKB1-mutant NSCLC.
Mutational inactivation of the LKB1 kinase is frequently observed in non–small cell lung cancer (NSCLC) subtypes including adenocarcinoma (ADC), squamous cell carcinoma (SCC) and adeno–squamous cell carcinomas (Ad-SCC), and leads to primary resistance to therapies that are effective in KRAS-mutant mice. Although LKB1 was initially defined as a tumor suppressor, recent reports implicate LKB1 in metabolic homeostasis, survival under stress conditions, and acceleration of mutant KRAS –driven tumorigenesis, prompting Li, Han, Li, and colleagues to address whether LKB1 promotes lung tumor progression via metabolic adaption. Loss of LKB1 in a KRAS-mutant NSCLC mouse model (KL) led to heterogeneous tumors composed of SCC and Ad-SCC in addition to ADC, indicative of ADC-to-SCC transdifferentiation (AST). This heterogeneity was associated with increased expression of glutathione (GSH) synthesis genes and reduced reactive oxygen species (ROS) levels in KL SCC compared with ADC. In line with this finding, LKB1 expression inversely correlated with ROS in human NSCLC, suggesting that LKB1 inactivation is associated with ROS accumulation and tumor plasticity. Indeed, ROS alleviation inhibited AST and led to decreased SCC and a higher incidence of ADC. Mechanistically, high levels of ROS in KL ADC were attributed to decreased activity of the pentose phosphatase pathway and the AMP kinase (AMPK)–acetyl CoA carboxylase (ACC) fatty acid oxidation axis in response to LKB1 inactivation. Reactivation of either pathway reduced ROS levels and inhibited AST, resulting in decreased SCC incidence. Analysis of human tumors confirmed a correlation between LKB1 deficiency and inactivation of the AMPK–ACC axis in both ADC and Ad-SCC. Furthermore, treatment of KL mice with the preclinical ROS-inducing agents piperlongumine or phenformin enhanced AST and increased SCC incidence, suggesting that AST may represent a potential mechanism to evade therapy. Together, these data highlight how loss of LKB1 drives redox imbalances that may contribute to treatment resistance via tumor cell plasticity.