LKB1: Can We Target an Hidden Target? Focus on NSCLC

Abstract

LKB1 (liver kinase B1) is a master regulator of several processes such as metabolism, proliferation, cell polarity and immunity. About one third of non-small cell lung cancers (NSCLCs) present LKB1 alterations, which almost invariably lead to protein loss, resulting in the absence of a potential druggable target. In addition, LKB1-null tumors are very aggressive and resistant to chemotherapy, targeted therapies and immune checkpoint inhibitors (ICIs). In this review, we report and comment strategies that exploit peculiar co-vulnerabilities to effectively treat this subgroup of NSCLCs. LKB1 loss leads to an enhanced metabolic avidity, and treatments inducing metabolic stress were successful in inhibiting tumor growth in several preclinical models. Biguanides, by compromising mitochondria and reducing systemic glucose availability, and the glutaminase inhibitor telaglenastat (CB-839), inhibiting glutamate production and reducing carbon intermediates essential for TCA cycle progression, have provided the most interesting results and entered different clinical trials enrolling also LKB1-null NSCLC patients. Nutrient deprivation has been investigated as an alternative therapeutic intervention, giving rise to interesting results exploitable to design specific dietetic regimens able to counteract cancer progression. Other strategies aimed at targeting LKB1-null NSCLCs exploit its pivotal role in modulating cell proliferation and cell invasion. Several inhibitors of LKB1 downstream proteins, such as mTOR, MEK, ERK and SRK/FAK, resulted specifically active on LKB1-mutated preclinical models and, being molecules already in clinical experimentation, could be soon proposed as a specific therapy for these patients. In particular, the rational use in combination of these inhibitors represents a very promising strategy to prevent the activation of collateral pathways and possibly avoid the potential emergence of resistance to these drugs. LKB1-null phenotype has been correlated to ICIs resistance but several studies have already proposed the mechanisms involved and potential interventions. Interestingly, emerging data highlighted that LKB1 alterations represent positive determinants to the new KRAS specific inhibitors response in KRAS co-mutated NSCLCs. In conclusion, the absence of the target did not block the development of treatments able to hit LKB1-mutated NSCLCs acting on several fronts. This will give patients a concrete chance to finally benefit from an effective therapy.

Repurposing Metformin for the Treatment of Atrial Fibrillation: Current Insights

“…LKB1 also targets cellular pathways other than those regulated by AMPK and therefore some of the effects of metformin may be independent of AMPK activation including, for instance, an increase in the production of catalase and superoxide dismutase and suppression of Bax-dependent caspase 3 mediated apoptosis. 242 , 243 …”

Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers

“…In general, targeting tumor suppressors has been a difficult challenge but LKB1 is an attractive target because of its role as master regulator of the AMPK as well as other metabolic pathways. Some reports, including from our collaborators, demonstrate the possibility of targeting metabolic vulnerabilities in KL tumors ( 1 , 4 , 14 , 15 , 24 , 25 ). Moreover, enthusiasm surrounding immune therapy in lung cancer has been tempered by the observation that LKB1 mutant tumors are “immune cold” exhibiting no objective response to immune checkpoint inhibitors and the ability to escape immune surveillance by silencing the STING pathway ( 6 , 18 ).…”

Recent progress in targeted therapy for non-small cell lung cancer

“…Treatment for STK11-mutated NSCLC is challenging, and research on STK11/LKB1 mutations as targets for NSCLC treatment deserves to be pushed forward. Data from a recent clinical trial suggested that inhibitors of mTOR and glutamine, such as everolimus and telaglenastat, exerted a therapeutic effect on NSCLC patients with STK11/LKB1 mutations (Ndembe et al, 2022;Sumbly and Landry, 2022).…”