STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Pons‐Tostivint, Elvire; Lugat, Alexandre; Fontenau, Jean-François; Denis, Marc G.; Bennouna, Jaafar

doi:10.3390/cells10113129

Cited by 42 publications

(34 citation statements)

References 89 publications

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“…A wide variety of tumors have shown STK11/LKB1 aberrancies [23][24][25]. Genetic anomalies such as loss of heterozygosity, insertion-deletion (indel) mutations, and chromosomal deletions are well-known causes of loss of function in genes [26]. Genetic mapping revealed that STK11 is located on chromosome subband 19p13.3 [27].…”

Section: Stk11/lkb1 Deficiency and Cancermentioning

confidence: 99%

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

Sumbly¹,

Landry²

2022

Cureus

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There are two major groups of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLCs can be further separated into three different categories: lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Pulmonary adenocarcinomas represent nearly half of all lung cancer cases and are known to be caused by smoking, certain occupational exposures, and specific genetic mutations. Scientists have noticed that most NSCLCs are driven by defects in the following genes: EGFR, BRAF, ALK, MET, and HER. Abnormalities in the STK11/LKB1 gene have also been shown to induce lung adenocarcinoma. LKB1-deficient cancer cells contain an overactive AMPK "energy sensor," which inhibits cellular death and promotes glucose, lipid, and protein synthesis via the mTOR protein complex. Studies have also discovered that the loss of STK11/LKB1 favors oncogenesis by creating an immunosuppressive environment for tumors to grow and accelerate events such as angiogenesis, epithelial-mesenchymal transition (EMT), and cell polarity destabilization. STK11/LKB1-mutant lung cancers are currently treated with radiotherapy with or without chemotherapy. Recent clinical trials studying the effects of glutaminase inhibitors, mTOR inhibitors, and anti-PD-L1 therapy in lung cancer patients have yielded promising results. This narrative review provides an overview of the STK11/LKB1 gene and its role in cancer development. Additionally, a summary of the LKB1/APMK/mTOR is provided.

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Section: Stk11/lkb1 Deficiency and Cancermentioning

confidence: 99%

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

Sumbly¹,

Landry²

2022

Cureus

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“…This is true for patients given with ICI both in first-line and second-line treatments, and considering both monotherapy and a combination of two ICIs ( 168 , 173 , 174 ). However, studies in which the LKB1 mutant tumors’ response to ICI was compared to that of chemotherapy, showed a similarly lower response to both treatments ( 43 , 175 ). Therefore, LKB1 mutations should probably be considered a prognostic factor, independently from the treatment type, rather than a predictive biomarker of ICIs resistance.…”

Section: Lkb1 and Immune Systemmentioning

confidence: 97%

“…In addition, STK11 is also active in modulation of the immune system. Its inactivation promotes the production of proinflammatory cytokines CXCL7, G-CSF and IL-6, which contribute to the accumulation of T cell suppressor neutrophils, with corresponding low CD4+/CD8+ T lymphocyte infiltration and low levels of PD-L1 (programmed cell death-1 ligand) ( 43 – 47 ).…”

Section: Introductionmentioning

confidence: 99%

“…However, as in almost all missense mutations, there is a complete loss of LKB1’s oncosuppressive function, since that these mutations directly affect its kinase domain or the domains that guarantee its cytoplasmic localization ( 9 , 48 , 49 ). These characteristics mean that STK11 mutated tumors cannot be treated either with direct targeted therapy, because the protein is completely absent, or with immunotherapy alone because of the “cold” tumor immune microenvironment ( 43 , 46 , 50 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…KEAP1 mutation prevalence in NSCLC is 15.8% [ 138 ]. Furthermore, STK11/LKB1 and KEAP1 mutations are associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8 + T cells and a neutrophil-enriched TME [ 139 ]. STK11/LKB1 - or KEAP1 -mutated NSCLC patients had a higher bTMB than wild-type patients, and KEAP1 -mutated patients had a higher PD-L1 expression (TC ≥ 50%/IC ≥ 50%: 25.00% vs. 14.54%), while STK11/LKB1 -mutated patients had lower PD-L1 expression (TC ≥ 50%/IC ≥ 50%: 7.89% vs. 15.90%) [ 136 ].…”

Section: Tumor/specific Genotypementioning

confidence: 99%

Predictive Markers for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Ushio

Murakami

Saito

2022

JCM

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Immune checkpoint inhibitors (ICIs) have dramatically improved the outcomes of non-small cell lung cancer patients and have increased the possibility of long-term survival. However, few patients benefit from ICIs, and no predictive biomarkers other than tumor programmed cell death ligand 1 (PD-L1) expression have been established. Hence, the identification of biomarkers is an urgent issue. This review outlines the current understanding of predictive markers for the efficacy of ICIs, including PD-L1, tumor mutation burden, DNA mismatch repair deficiency, microsatellite instability, CD8+ tumor-infiltrating lymphocytes, human leukocyte antigen class I, tumor/specific genotype, and blood biomarkers such as peripheral T-cell phenotype, neutrophil-to-lymphocyte ratio, interferon-gamma, and interleukin-8. A tremendous number of biomarkers are in development, but individual biomarkers are insufficient. Tissue biomarkers have issues in reproducibility and accuracy because of intratumoral heterogeneity and biopsy invasiveness. Furthermore, blood biomarkers have difficulty in reflecting the tumor microenvironment and therefore tend to be less predictive for the efficacy of ICIs than tissue samples. In addition to individual biomarkers, the development of composite markers, including novel technologies such as machine learning and high-throughput analysis, may make it easier to comprehensively analyze multiple biomarkers.

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STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact

Cited by 42 publications

References 89 publications

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

Unraveling the Role of STK11/LKB1 in Non-small Cell Lung Cancer

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

Predictive Markers for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

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