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

Abstract

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.

Prognostic implications of STK11 with different mutation status and its relationship with tumor-infiltrating immune cells in non-small cell lung cancer

“…Another study reported the same results, that is, OS was significantly shorter for patients with STK11 mutation (STK11 Mut 14.2 months vs. STK11 Wt 27.0 months) (28). Among NSCLC patients, the STK11 mutation was associated with a worse outcome for patients receiving systemic antitumor therapy, but not immune checkpoint inhibition therapy (13). Consistent with previous reports, our findings indicated that the presence of STK11 mutation was associated with poor prognosis in NSCLC.…”

“…In preclinical models, STK11 inactivation often led to cancer progression and metastasis and was associated with indolent tumor immune microenvironment, exhibiting as a reduced density of infiltrating cytotoxic CD8 + T lymphocytes, decreased PD-(L)1 expression and a neutrophil-rich tumor microenvironment (7). Loss of STK11 function was identified as a potential feature of malignant tumors in a variety of malignancies, such as cervical cancer (23), meningiomas (24), cholangiocarcinoma (25) and lung cancer (13). STK11 affects tumor cell growth through various important cellular pathways, and gene mutations can affect pathways such as AMPK, STING, and vascular endothelial growth factor, leading to immune suppression and changes in the metabolic environment, which resulted in tumor growth (10).…”

“…It should be noted that a large proportion of LUAD patients have multi-gene co-mutations, presenting with significantly different prognoses (32). For instance, STK11 may have co-mutations with KRAS, KEAP1 or EGFR (8,13,29,32,33), and some real-world study showed that patients with co-mutation of STK11 and KEAP1 or KRAS was associated with significantly shorter survival (33).…”

“…through AMPK signaling pathway and 12 AMPK related kinases (12). The mutation rate of STK11 in lung adenocarcinoma was 16.7%, and the co-mutation rate with KRAS was 25.4% (12,13). The inactivation of STK11 gene or its protein product LKB1 is related to the cold tumor immune environment, which is accompanied by the decrease of infiltrating cytotoxic CD8+ T lymphocytes in both human tumors and genetically engineered mouse models (14).…”