Serine/threonine kinase 11 (STK11) mutations and immunotherapy resistance in patients with non-small cell lung cancer.

Uba, Richie Onwuchekwa; Raez, Luis E.; Dumais, Katerine; Gentile, Frank T.; Powery, H.; Domingo, Gelenis; Izquierdo, P. Frontera

doi:10.1200/jco.2020.38.15_suppl.e15055

Cited by 5 publications

(3 citation statements)

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“…19 It was shown to worsen the treatment outcome in patients receiving both chemotherapy and ICI, though prognostic significance is less pronounced in the cohort of patients receiving ICI. 6,16,20,21 Consequently, STK11 may play both a prognostic and predictive role, which agrees with our results. Since STK11 mutations are frequently observed in PD-L1-low/TMB-low patients 22,23 this marker may provide an additional molecular-defined cohort of patients with NSCLC, which may benefit more from immunotherapy.…”

Section: Resultssupporting

confidence: 92%

Impact of the STK11/KRAS co-mutation on the response to immunotherapy in a real-world pan-cancer cohort

Olsen,

Lebedeva,

Nosova

et al. 2023

Tumori

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Introduction: Immune checkpoint inhibitors are highly effective in treating various cancers. We analyzed the significance of the KRAS/STK11 co-mutation in relation to the efficacy of immune checkpoint inhibitors in pan-cancer patient cohort. Methods: We analyzed data from open-access research: MSK-IMPACT (molecular profiling data from patients receiving systemic antitumor therapy) and MSK-TMB (molecular profiling data from patients receiving immune checkpoint inhibitors). In both studies, high throughput sequencing was used for molecular profiling. Results: A total of 10,336 patients receiving antitumor therapy (MSK-IMPACT study) and 1661 patients receiving immune checkpoint inhibitors (MSK-TMB study) were included in the analysis. Co-mutation STK11/KRAS was found in 156 (1.5%) and 46 (2.8%) patients in the two studies, respectively. Most patients with the STK11/KRAS co-mutation had non-small cell lung cancer (83% and 85% in the two studies, respectively). Among non-small cell lung cancer patients, the STK11 mutation was associated with a worse outcome for patients receiving systemic antitumor therapy, but not immune checkpoint inhibition therapy (HR for OS 1.90 [95% CI 1.36-2.65] and 1.44 [95% CI 0.88-2.37]). Co-mutation STK11/KRAS was also not associated with patient outcome in any of the studies (HR for OS 0.93 [95% CI 0.56-1.52] and 1.09 [95% CI 0.54-2.19]). High tumor mutational burden was associated with better outcome in the cohort of patients receiving immune checkpoint inhibitors. An analogous analysis among patients in the pan-cancer cohort (excluding patients with non-small cell lung cancer) showed STK11 mutations and high tumor mutational burden have a predictive role for the efficacy of immune checkpoint inhibitors, but not STK11/KRAS co-mutation. Conclusions: Co-mutation STK11/KRAS is common among patients with non-small cell lung cancer and is not an independent predictive marker for the efficacy of immune checkpoint inhibitors. Further studies are required to clarify the role of STK11 mutations in immune checkpoint inhibitor treatment response.

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Section: Resultssupporting

confidence: 92%

Impact of the STK11/KRAS co-mutation on the response to immunotherapy in a real-world pan-cancer cohort

Olsen,

Lebedeva,

Nosova

et al. 2023

Tumori

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“…Furthermore, the KRAS p.G12C mutation was observed in the presence of high STK11 mutation levels in this study, as has recently been reported by others in a single treatment center [39]. STK11 mutations have been observed at a high rate in NSCLC and even higher in KRAS mutated NSCLC; the KRAS p.G12C/STK11 co-mutation pattern has been associated with lower overall survival and resistance to immune checkpoint inhibitors [38,[40][41][42][43][44]. KEAP1 mutations were prevalent in the G12C cohort, as well as the other cohorts in this study; although others have reported even higher levels of KEAP1 co-mutation [39].…”

Section: Discussionsupporting

confidence: 85%

A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease

Spira

Aggarwal

et al. 2021

Lung Cancer

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The KRAS p.G12C mutation, prevalent in non-small-cell lung cancer (NSCLC), has only recently become a viable target. Here we present results of the largest retrospective observational study analyzing KRAS p.G12C in patients with advanced NSCLC. Materials and Methods: Adults with advanced NSCLC (All Advanced NSCLC cohort) and subcohorts with different mutation profiles (KRAS p.G12C [G12C] and KRAS/EGFR/ALK wild type [Triple WT]) diagnosed January 2011 to March 2019 were selected from a US clinico-genomic database; treatment-related characteristics, molecular profiles, real-world overall (rwOS) and progression-free survival (rwPFS) were analyzed. Results: Demographics were similar across cohorts, with more smokers and nonsquamous cell carcinoma histology in the G12C cohort. KRAS p.G12C was nearly mutually exclusive (≤1.2 %) with known actionable driver mutations, but non-driver co-mutations were common (STK11, 21.5 %; KEAP1, 7.0 %; TP53, 48.0 %). Among G12C patients, 20 % had no documentation of receiving systemic therapy. Across treated G12C patients, 67 % received immune checkpoint inhibitors; first-line usage increased from 0% (2014) to 81 % (2019). Among G12C patients, median (95 % CI) rwOS was 12.0 (9.6-15.3), 9.5 (8.1-13.1), and 6.7 (5.9-10.7) months after first, second, and third line of therapy, respectively; median (95 % CI) rwPFS was 5.0 (4.4-5.8), 4.0 (2.8-5.3), and 3.1 (2.4-4.3) months. Outcomes for the G12C subcohort were similar to those for all patients (All Advanced NSCLC cohort). Mutations in STK11/KEAP1 were associated with poorer survival across all cohorts. Conclusion:The poor outcomes associated with KRAS p.G12C mutated advanced NSCLC indicate an unmet need for more effective novel treatments.Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; CGDB, clinico-genomic database; CGP, comprehensive genomic profiling; EGFR, epidermal growth factor receptor; EHR, electronic health records; FH-FMI, Flatiron Health-Foundation Medicine; G12C, patients with KRAS p.G12C mutated NSCLC included in study; KEAP1, Kelch-like ECH-associated protein 1 oncogene; KRAS, Kirsten rat sarcoma viral oncogene homolog; KRAS p.G12C, codon 12 glycine-tocysteine substitution of KRAS; MET, mesenchymal-epithelial transition; NGS, next-generation sequencing; NSCLC, non-small-cell lung cancer; NTRK1-3, neurotrophic tyrosine kinases 1-3 gene; PD-1, programmed death 1; PD-L1, programmed death ligand 1; RAS, rat sarcoma viral oncogene homolog; RECIST, Response Evaluation Criteria in Solid Tumors; RET, rearranged-during-transfection gene; ROS1, ROS proto-oncogene 1; rwOS, real-world overall survival; rwPFS, real-world progression-free survival; STK11/LKB1, serine/threonine kinase 11, liver kinase B1; TP53, tumor protein p53; Triple WT, KRAS/EGFR/ALK wild-type; VEGF, vascular endothelial growth factor.

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“…Many retrospective clinical studies investigated LKB1 mutations as a negative determinant of immunotherapy response ( 50 , 168 – 170 ). Indeed, patients with non-squamous LKB1 -mutated NSCLC tumors do not respond to ICI or they general have dramatically lower survival and progression-free survival ( 50 , 171 , 172 ). 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 ).…”

Section: Lkb1 and Immune Systemmentioning

confidence: 99%

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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Serine/threonine kinase 11 (STK11) mutations and immunotherapy resistance in patients with non-small cell lung cancer.

Cited by 5 publications

References 0 publications

Impact of the STK11/KRAS co-mutation on the response to immunotherapy in a real-world pan-cancer cohort

Impact of the STK11/KRAS co-mutation on the response to immunotherapy in a real-world pan-cancer cohort

A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease

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

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