bims-meluca 2023-09-17 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–09–17
twelve papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Survival and biomarkers for cachexia in non-small cell lung cancer receiving immune checkpoint inhibitors.
Plasma levels of 12 different cytokines correlate to PD-1 inhibitor combined chemotherapy responses in advanced non-small-cell lung cancer patient.
Differences in serum cytokine levels distinguish between clinically noninvasive lung adenocarcinoma and invasive lung adenocarcinoma: A cross-sectional study.
Lipid metabolism-related gene signatures for predicting the prognosis of lung adenocarcinoma.
Predicting lung adenocarcinoma prognosis, immune escape, and pharmacomic profile from arginine and proline-related genes.
Bulk RNA-seq and scRNA-seq reveal SLC7A11, a key regulatory molecule of ferroptosis, is a prognostic-related biomarker and highly related to the immune system in lung adenocarcinoma.
Characterization of chemoresistant human non-small cell lung cancer cells by metabolic and lipidomic profiling.
Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.
Plasma extracellular vesicle long RNAs predict response to neoadjuvant immunotherapy and survival in patients with non-small cell lung cancer.
High level of C-reactive protein as a predictive factor for immune-related adverse events of immune checkpoint inhibitors in non-small cell lung cancer: a retrospective study.
Comparative bioinformatic analysis of KRAS, STK11 and KEAP1 (co-)mutations in non-small cell lung cancer with a special focus on KRAS G12C.
The possibility of mutations of RAS signaling genes and/or TP53 in combination as a negative prognostic impact on pathological stage I non-small cell lung cancer.

Cancer Med. 2023 Sep 15.

Survival and biomarkers for cachexia in non-small cell lung cancer receiving immune checkpoint inhibitors.

Daiki Murata, Koichi Azuma, Norikazu Matsuo, Kenta Murotani, Goushi Matama, Akihiko Kawahara, Tetsuro Sasada, Takaaki Tokito, Tomoaki Hoshino.

   BACKGROUND: The presence of cachexia negatively impacts the prognosis of patients with cancer. However, the mechanisms behind the development of cachexia and its prognostic impact on immunotherapy efficacy are not fully understood.
MATERIALS AND METHODS: We retrospectively screened patients with advanced or recurrent non-small cell lung cancer (NSCLC) who received PD-1/PD-L1 inhibitor monotherapy. Among 183 patients, pre-treatment plasma samples were available from 100 patients. We defined cancer cachexia as weight loss of at least 5% during the past 6 months or weight loss of at least 2% and BMI <20. We analyzed 75 soluble immune mediators in pre-treatment plasma samples to explore the possible mechanisms behind the development of cancer cachexia. We also investigated whether cancer cachexia affects prognosis.
RESULTS: Among 100 patients, 35 had cancer cachexia. Logistic regression analysis identified ghrelin, c-reactive protein (CRP), pentraxin-3 (PTX-3), and osteopontin (OPN) as factors associated with cachexia. Patients with cachexia had worse progression-free survival (PFS) and overall survival (OS), although we did not detect statistically significant differences. Analyzing the soluble immune mediators associated with cachexia, the combination of cachexia and PTX-3 or OPN expression levels was predictive for PFS and the combination of cachexia and CRP or OPN expression levels was predictive for OS.
CONCLUSIONS: Pre-treatment ghrelin, CRP, PTX-3, and OPN may be associated with cachexia. Among patients with NSCLC who received PD-1/L1 inhibitor monotherapy, those with cachexia had worse survival than those without cachexia. Larger studies will be required to confirm our data and better understand the mechanisms behind the development of cachexia.

Keywords:  CRP; NSCLC; PD-1 inhibitor; cachexia; chemokine; cytokine

DOI:  https://doi.org/10.1002/cam4.6549
Int Immunopharmacol. 2023 Sep 08. pii: S1567-5769(23)01213-4. [Epub ahead of print]124(Pt A): 110888

Plasma levels of 12 different cytokines correlate to PD-1 inhibitor combined chemotherapy responses in advanced non-small-cell lung cancer patient.

Yun Peng, Qiufeng Qi, Ming Zhu, Yaping Zhang, Yanqing Bao, Yongping Liu.

BACKGROUND: Targeted anti-programmed death receptor 1 (PD-1) monoclonal antibodies, when combined with chemotherapy, have shown improved outcomes in non-small cell lung cancer (NSCLC). However, it is important to note that not all patients benefit from this treatment, and there is a pressing need for more reliable efficacy measures and potential predictors of outcome. Cytokines, which are important molecules in the immune system, have been considered as potential biomarkers in clinical settings, but their precise clinical use remains unclear. In this study, our objective was to assess whether the levels of cytokines in the patient's blood sample are associated with tumor response to anti-PD-1 monoclonal antibodies combined with chemotherapy as well as the survival of patients with advanced non-small cell lung cancer.
MATERIALS AND METHODS: A total of 12 plasma cytokines were measured in advanced NSCLC patients (n = 35) and healthy individuals (n = 26) using multi-microsphere flow immunofluorescence. The relationship between cytokine levels and clinical response was analyzed using nonparametric Wilcoxon matched-pair ranked tests. Progression-free survival (PFS) time was recorded for all patients through radiographic outcome assessment and telephone follow-up. Survival curves were generated using the Kaplan-Meier and log-rank tests, and the thresholds for cytokines were determined using receiver operating characteristic analysis (ROC).
RESULTS: The expression levels of interleukin IL-6, IL-1 β, IFN-γ, IL-12p70, and TNF-α were significantly lower in the control group than those in the NSCLC group (p = 0.001, p = 0.0028, p = 0.019, p = 0.0001, p = 0.0021). High IL-10 levels at baseline and after 4 cycles of treatment conferred a worse prognosis; in addition, high TNF-α levels in patients after two cycles of immunochemotherapy suggested drug resistance. High levels of IL-6 and IFN-γ in patients undergoing four cycles of immunochemotherapy were associated with worse PFS.
CONCLUSIONS: Our study suggests that cytokines can serve as detection indicators for predicting efficacy in non-small cell lung cancer patients undergoing anti-PD-1 combined with chemotherapy treatment. Elevated levels of IL-10, TNF-α, IL-6, and IFN-γ in the plasma may indicate a higher likelihood of experiencing a worse clinical outcome.

DOI: https://doi.org/10.1016/j.intimp.2023.110888
Health Sci Rep. 2023 Sep;6(9): e1522

Differences in serum cytokine levels distinguish between clinically noninvasive lung adenocarcinoma and invasive lung adenocarcinoma: A cross-sectional study.

Bingjie Zeng, Xianzhao Wang, Yueyang Qin, Leiqun Cao, Congcong Zhang, Fanyu Meng, Changqiang Chen, Jiayi Wang, Lifang Ma.

   Background: Lung cancer incidence and mortality remain high and are now the leading cause of cancer-related death. Lung adenocarcinoma (LUAD) is one of the main histological subtypes of lung cancer. Previous studies have shown the role of inflammation in the development of lung cancer, but the relationship between cytokines and LUAD is still unclear. To further differentiate and explore the association of cytokines with the risk of non-invasive and invasive LUAD, we studied and assessed serum cytokine levels in patients with two types of LUAD.
Methods: A cohort study of 90 non-invasive LUAD and 90 invasive LUAD was retrospectively included, and the clinical characteristics were recorded in detail. The differences in the levels of 12 serum cytokines (IFN-α, IFN-γ, IL-10, IL-12P70, IL-17A, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, and TNF-α) between the two groups of patients with LUAD were analyzed and evaluated. And we evaluated the clinical value of cytokine differential diagnosis of invasive LUAD based on receiver operating characteristics (ROC) curves.
Results: The mean age of the patients was 56.6 years, and the proportions of males and females were 38.9% and 61.1%, respectively. IFN-α, IL-1β, IL-2, IL-6, TNF-α, IL-4, and IL-8 were significantly increased in patients with invasive LUAD compared with the non-invasive LUAD group. Further research found that smoking is an important factor, with changes in the four cytokines IL-1β, IL-6, IL-8, and TNF-α being significantly higher in the smoking group of patients with invasive LUAD. It can be seen from the area under the curve that IL-1β and IL-2 have a significant differential diagnosis.
Conclusions: We observed differences in preoperative serum cytokine levels between patients with invasive and non-invasive LUAD, which may serve as potential serum biomarkers for clinical differential diagnosis and disease progression assessment.

Keywords:  cytokine; inflammation; invasive lung adenocarcinoma; non‐invasive lung adenocarcinoma

DOI:  https://doi.org/10.1002/hsr2.1522
Transl Cancer Res. 2023 Aug 31. 12(8): 2099-2114

Lipid metabolism-related gene signatures for predicting the prognosis of lung adenocarcinoma.

Xueting Cao, Boya Wu, Yingzheng Hou, Jing Chen.

   Background: Lung cancer is one of the most common epithelial malignancies worldwide, accounting for the highest number of new cases and deaths. Metabolism is the sum of chemical reactions that produce energy to keep an organism alive. Several studies have shown that glucose and lipid metabolic disorders are common phenomena related to cancer cell genesis and progression.
Methods: We screened the differentially expressed genes (DEGs) of lung adenocarcinoma (LUAD) samples of The Cancer Genome Atlas (TCGA) database, the Gene Set Enrichment Analysis (GSEA), and Gene Card database metabolism-related data, the metabolism-related DEGs of LUAD, as well as the univariate Cox regression analysis genes, for identifying significant outcome-related genes. The least absolute shrinkage and gene selection operator (LASSO) analysis was performed to establish the best risk model.
Results: Our study aimed to establish a lipid metabolism-related model for predicting LUAD prognosis. Furthermore, our model's prognosis prediction power was evaluated by survival analysis. This study finally identified 11 DEGs related to lipid metabolism that were significantly associated with the prognosis of lung adenocarcinoma. It provided a new idea for the treatment of high-risk lung adenocarcinoma patients.
Conclusions: The constructed clinical prognosis model of lung adenocarcinoma related to lipid metabolism provides a new idea for clinical treatment of lung adenocarcinoma.

Keywords:  Lipid metabolism; lung adenocarcinoma (LUAD); prognosis

DOI:  https://doi.org/10.21037/tcr-23-375
Sci Rep. 2023 Sep 14. 13(1): 15198

Predicting lung adenocarcinoma prognosis, immune escape, and pharmacomic profile from arginine and proline-related genes.

Ziqiang Wang, Jing Zhang, Shuhua Shi, Hongyu Ma, Dongqin Wang, Chao Zuo, Qiang Zhang, Chaoqun Lian.

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease that ranks first in morbidity and mortality. Abnormal arginine metabolism is associated with inflammatory lung disease and may influence alterations in the tumor immune microenvironment. However, the potential role of arginine and proline metabolic patterns and immune molecular markers in LUAD is unclear. Gene expression, somatic mutations, and clinicopathological information of LUAD were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was performed to identify metabolic genes associated with overall survival (OS). Unsupervised clustering divided the sample into two subtypes with different metabolic and immunological profiles. Gene set enrichment analysis (GESA) and gene set variation analysis (GSVA) were used to analyze the underlying biological processes of the two subtypes. Drug sensitivity between subtypes was also predicted; then prognostic features were developed by multivariate Cox regression analysis. In addition, validation was obtained in the GSE68465, and GSE50081 dataset. Then, gene expression, and clinical characterization of hub genes CPS1 and SMS were performed; finally, in vitro validation experiments for knockdown of SMS were performed in LUAD cell lines. In this study, we first identified 12 arginine and proline-related genes (APRGs) significantly associated with OS and characterized the clinicopathological features and tumor microenvironmental landscape of two different subtypes. Then, we established an arginine and proline metabolism-related scoring system and identified two hub genes highly associated with prognosis, namely CPS1, and SMS. In addition, we performed CCK8, transwell, and other functional experiments on SMS to obtain consistent results. Our comprehensive analysis revealed the potential molecular features and clinical applications of APRGs in LUAD. A model based on 2 APRGs can accurately predict survival outcomes in LUAD, improve our understanding of APRGs in LUAD, and pave a new pathway to guide risk stratification and treatment strategy development for LUAD patients.

DOI: https://doi.org/10.1038/s41598-023-42541-z
Medicine (Baltimore). 2023 Sep 15. 102(37): e34876

Bulk RNA-seq and scRNA-seq reveal SLC7A11, a key regulatory molecule of ferroptosis, is a prognostic-related biomarker and highly related to the immune system in lung adenocarcinoma.

Xiaoyu Wu, Sheng Wang, Kaifang Chen.

Lung adenocarcinoma (LUAD) is the most common pathological subtype of lung cancer. Ferroptosis is an iron-dependent, non-apoptotic cell death mode, highly correlated with the tumorigenesis and progression of multiple cancers. Solute carrier family 7 member 11 (SLC7A11) maintains the anti-porter activity of cysteine and glutamate to regulate ferroptosis. We collected bulk RNA-seq and scRNA-seq from The Cancer Genome Altas and Gene Expression Omnibus databases. Then, we extracted the expression level of SLC7A11 to perform the differential expression analysis between normal tissues and LUAD tissues. Then, we applied survival, univariate, and multivariate Cox regression analyses to investigate the predictive value of SLC7A11 in LUAD. Gene set enrichment analysis was used to explore the underlying molecular mechanisms of SLC7A11 in LUAD. Finally, we analyzed the relationship of SLC7A11 to the immune status and the curative effect of immunotherapy. The expression level of SLC7A11 in LUAD tissues was markedly increased. The survival analysis, univariate and multivariate Cox regression analysis showed that SLC7A11 was a negative factor for the prognosis of LUAD patients. Gene set enrichment analysis revealed that several immune-related pathways were enriched in the low-level group. The lower SLC7A11 level has a better therapeutic effect of immunotherapy and less probability of immune escape and dysfunction. SLC7A11 was a prognostic-related biomarker and closely correlated with the immune status and therapeutic effect of immunotherapy in LUAD, which could be an effective biomarker for evaluating the prognosis and the therapeutic efficacy of immunotherapy.

DOI: https://doi.org/10.1097/MD.0000000000034876
Metabolomics. 2023 Sep 10. 19(9): 80

Characterization of chemoresistant human non-small cell lung cancer cells by metabolic and lipidomic profiling.

Ji Won Lee, Hwanhui Lee, Yoon Shik Chun, Junyoung Ahn, Jeong Yong Moon, Dae Kyeong Kim, Somi Kim Cho, Hyung-Kyoon Choi.

   INTRODUCTION: Lung cancer is one of the most malignant cancers and the leading cause of cancer-related deaths worldwide, while acquired chemoresistance would represent a major problem in the treatment of non-small cell lung cancer (NSCLC) because of the reduced treatment effect and increased rates of recurrence.
METHODS: To establish the chemoresistant NSCLC cells, doxorubicin was treated to A549 cells over 3 months at gradually increasing concentrations from 0.03 to 0.5 µM. Real-time PCR and Western blotting were employed for investigating mRNA and protein expression of the glutathione peroxidase (GPX) protein family and multidrug resistance protein 1 (MRP1) in A549 and A549/CR cells. We also employed gas chromatography mass-spectrometry and nano electrospray ionization mass-spectrometry coupled with multivariate statistical analysis to characterize the unique metabolic and lipidomic profiles of chemoresistant NSCLC cells in order to identify potential therapeutic targets.
RESULTS: Reactive oxygen species levels were decreased, and mRNA and protein levels of GPX2 and multidrug resistance protein 1 (MRP1) were increased in A549/CR. We identified 87 metabolites and intact lipid species in A549 and A549/CR. Among these metabolites, lactic acid, glutamic acid, glycine, proline, aspartic acid, succinic acid, and ceramide, alongside the PC to PE ratio, and arachidonic acid-containing phospholipids were suggested as characteristic features of chemoresistant NSCLC cells (A549/CR).
CONCLUSIONS: This study reveals characteristic feature differences between drug-resistance NSCLC cells and their parental cells. We suggest potential therapeutic targets in chemoresistant NSCLC. Our results provide new insight into metabolic and lipidomic alterations in chemoresistant NSCLC. This could be used as fundamental information to develop therapeutic strategies for the treatment of chemoresistant NSCLC patients.

Keywords:  Chemoresistance; Lipidomic profiling; Metabolic profiling; Non-small cell lung cancer; Potential therapeutic targets

DOI:  https://doi.org/10.1007/s11306-023-02045-3
Front Immunol. 2023 ;14 1204126

Novel XBP1s-independent function of IRE1 RNase in HIF-1α-mediated glycolysis upregulation in human macrophages upon stimulation with LPS or saturated fatty acid.

Margaud Iovino, Megan Colonval, Chloé Wilkin, Laurent L'homme, Cédric Lassence, Manon Campas, Olivier Peulen, Pascal de Tullio, Jacques Piette, Sylvie Legrand-Poels.

  In obesity, adipose tissue infiltrating macrophages acquire a unique pro-inflammatory polarization, thereby playing a key role in the development of chronic inflammation and Type 2 diabetes. Increased saturated fatty acids (SFAs) levels have been proposed to drive this specific polarization. Accordingly, we investigated the immunometabolic reprogramming in SFA-treated human macrophages. As expected, RNA sequencing highlighted a pro-inflammatory profile but also metabolic signatures including glycolysis and hypoxia as well as a strong unfolded protein response. Glycolysis upregulation was confirmed in SFA-treated macrophages by measuring glycolytic gene expression, glucose uptake, lactate production and extracellular acidification rate. Like in LPS-stimulated macrophages, glycolysis activation in SFA-treated macrophages was dependent on HIF-1α activation and fueled the production of pro-inflammatory cytokines. SFAs and LPS both induced IRE1α endoribonuclease activity, as demonstrated by XBP1 mRNA splicing, but with different kinetics matching HIF-1α activation and the glycolytic gene expression. Interestingly, the knockdown of IRE1α and/or the pharmacological inhibition of its RNase activity prevented HIF-1α activation and significantly decreased glycolysis upregulation. Surprisingly, XBP1s appeared to be dispensable, as demonstrated by the lack of inhibiting effect of XBP1s knockdown on glycolytic genes expression, glucose uptake, lactate production and HIF-1α activation. These experiments demonstrate for the first time a key role of IRE1α in HIF-1α-mediated glycolysis upregulation in macrophages stimulated with pro-inflammatory triggers like LPS or SFAs through XBP1s-independent mechanism. IRE1 could mediate this novel function by targeting other transcripts (mRNA or pre-miRNA) through a mechanism called regulated IRE1-dependent decay or RIDD. Deciphering the underlying mechanisms of this novel IRE1 function might lead to novel therapeutic targets to curtail sterile obesity- or infection-linked inflammation.

Keywords:  HIF-1α; IRE1α; glycolysis; inflammation; macrophages; saturated fatty acid

DOI:  https://doi.org/10.3389/fimmu.2023.1204126
Pharmacol Res. 2023 Sep 12. pii: S1043-6618(23)00277-3. [Epub ahead of print]196 106921

Plasma extracellular vesicle long RNAs predict response to neoadjuvant immunotherapy and survival in patients with non-small cell lung cancer.

Wei Guo, Bolun Zhou, Liang Zhao, Qilin Huai, Fengwei Tan, Qi Xue, Fang Lv, Shugeng Gao, Jie He.

  Neoadjuvant immunotherapy has brought new hope for patients with non-small cell lung cancer (NSCLC). However, limited by the lack of clinically feasible markers, it is still difficult to select NSCLC patients who respond well and to predict patients' clinical outcomes before the treatment. Before the treatment, we isolated plasma extracellular vesicles (EVs) from three cohorts (discovery, training and validation) of 78 NSCLC patients treated with neoadjuvant immunotherapy. To identify differentially-expressed EV long RNAs (exLRs), we employed RNA-seq in the discovery cohort. And we subsequently used qRT-PCR to establish and validate the predictive signature in the other two cohorts. We have identified 8 candidate exLRs from 27 top-ranked exLRs differentially expressed between responders and non-responders, and tested their expression with qRT-PCR in the training cohort. We finally identified H3C2 (P = 0.029), MALAT1 (P = 0.043) and RPS3 (P = 0.0086) significantly expressed in responders for establishing the predictive signature. Integrated with PD-L1 expression, our signature performed well in predicting immunotherapeutic responses in the training (AUC=0.892) and validation cohorts (AUC=0.747). Furthermore, our signature was proven to be a predictor for favorable prognosis of patients treated with neoadjuvant immunotherapy, which demonstrates the feasibility of our signature in clinical practices (P = 0.048). Our results demonstrate that the exLR-based signature could accurately predict responses to neoadjuvant immunotherapy and prognosis in NSCLC patients.

Keywords:  Extracellular vesicles; Long RNAs; Neoadjuvant immunotherapy; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/j.phrs.2023.106921
J Thorac Dis. 2023 Aug 31. 15(8): 4237-4247

High level of C-reactive protein as a predictive factor for immune-related adverse events of immune checkpoint inhibitors in non-small cell lung cancer: a retrospective study.

Ren Onodera, Shinji Chiba, Satoru Nihei, Itaru Fujimura, Masachika Akiyama, Yu Utsumi, Hiromi Nagashima, Kenzo Kudo, Makoto Maemondo.

   Background: Several risk factors for the immune-related adverse events (irAEs) during treatment with immune checkpoint inhibitors (ICIs) have been reported, of which include high levels of C-reactive protein (CRP). In this study, we aim to evaluate CRP levels before ICIs treatments as potential predictive biomarkers of irAEs incidence rate and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC).
Methods: Between December 1, 2015 to December 31, 2019, we retrospectively collected all adult patients with NSCLC who received at least one dose of an ICI targeting the PD-1/PD-L1 axis at the Iwate Medical University Hospital in Japan. In this study the patients were categorized into low and high groups with a cut-off value of 10 mg/L as the baseline level of CRP before the ICI treatment. The primary endpoint was relationship between CRP levels at baseline and incidence of irAEs. The secondary endpoints were the relationship of progression-free survival (PFS) and OS.
Results: A total of 101 irAEs, and 25 severe irAEs were observed. The incidence of the most irAEs was higher in the high CRP group compared to the low CRP group (54.4% vs. 34.5%, respectively, P=0.003). The most frequent irAEs were skin rush (28.8%), followed by pneumonitis (19.2%), hypothyroidism (15.4%), and hepatotoxicity (9.6%). The most common grade 3 or 4 irAEs was pneumonitis (7.9%), which tended to be more frequent in the high CRP group. In multivariate analysis, patients with high CRP levels had an adjusted OR of 2.41 and were associated with an increased risk of developing irAEs (95% CI: 1.16-4.43, P=0.020). The high CRP group was related with shorter PFS compared to the low CRP group (2.2 vs. 3.3 months, respectively, P=0.006). The high CRP group were also related with shorter OS compared to the low CRP group (8.9 vs. 39.1 months, respectively, P<0.001).
Conclusions: The results suggest that higher level of pretreatment CRP is involved in the development of irAE and poor prognosis. Identification of patients at high risk of irAEs would be of great help. Future multicenter prospective studies are needed to expand on this study.

Keywords:  C-reactive protein (CRP); Non-small cell lung cancer (NSCLC); biomarkers; immune checkpoint inhibitors (ICIs); immune-related adverse events (irAEs)

DOI:  https://doi.org/10.21037/jtd-23-85
Lung Cancer. 2023 Sep 09. pii: S0169-5002(23)00899-1. [Epub ahead of print]184 107361

Comparative bioinformatic analysis of KRAS, STK11 and KEAP1 (co-)mutations in non-small cell lung cancer with a special focus on KRAS G12C.

Myriam Boeschen, Christina Katharina Kuhn, Hubert Wirtz, Hans-Jürgen Seyfarth, Armin Frille, Florian Lordick, Ulrich T Hacker, Ulrike Obeck, Mathias Stiller, Hendrik Bläker, Maximilian von Laffert.

OBJECTIVES: Mutations in STK11 (STK11MUT) and KEAP1 (KEAP1MUT) occur frequently in non-small cell lung cancer (NSCLC) and are often co-mutated with KRAS. Several studies linked the co-occurrence of KRASMUT + STK11MUT, as well as KRASMUT + KEAP1MUT to reduced response to immune checkpoint inhibitors (ICI) and even a negative impact on survival. Data focusing STK11 + KEAP1 co-mutations or the triple mutation (KRAS + STK11 + KEAP1) are scarce. The recent availability of KRAS-G12C inhibitors increases the clinical relevance of those co-mutations in KRAS-mutated NSCLC.
MATERIALS AND METHODS: We present a comprehensive bioinformatic analysis encompassing six datasets retrieved from cBioPortal.
RESULTS: Independent of the treatment, triple mutations and STK11MUT + KEAP1MUT were significantly associated with a reduced overall survival (OS). Across treatments, OS of patients with a KRAS G12C triple mutation was significantly reduced compared to patients with KRAS G12C-only. Under ICI-therapy, there was no significant difference in OS between patients harboring the KRAS G12C-only and patients with the KRAS G12C triple mutation, but a significant difference between patients harboring KRAS non-G12C and KRAS non-G12C triple mutations. Triple mutated primary tumors showed a significantly increased frequency of distant metastases to bone and adrenal glands compared to KRAS-only mutated tumors. Additionally, our drug response analysis in cancer cell lines harboring the triple mutations revealed the WNT pathway inhibitor XAV-939 as a potential future drug candidate for this mutational situation.
CONCLUSION: The triple mutation status may serve as a negative prognostic and predictive factor across treatments compared to KRASMUT-only. KRAS G12C generally seems to be a negative predictive marker for ICI-therapy.

DOI: https://doi.org/10.1016/j.lungcan.2023.107361
Cancer Med. 2023 Sep 15.

The possibility of mutations of RAS signaling genes and/or TP53 in combination as a negative prognostic impact on pathological stage I non-small cell lung cancer.

Takayuki Honda, Katsutoshi Seto, Satoshi Endo, Akira Takemoto, Kousuke Tanimoto, Masashi Kobayashi, Masatake Kitano, Rie Sakakibara, Takahiro Mitsumura, Hironori Ishibashi, Johji Inazawa, Toshihiro Tanaka, Yasunari Miyazaki, Kenichi Okubo.

   BACKGROUND: The recurrence rate of non-small cell lung cancer (NSCLC) is as high as 30%, even in the cancer with pathological stage I disease. Therefore, identifying factors predictive of high-risk pathological recurrence is important. However, few studies have examined the genetic status of these tumors and its relationship to prognosis.
MATERIALS AND METHODS: A cohort of 328 cases of primary lung cancer that underwent complete resection at Tokyo Medical and Dental University (TMDU) was screened for 440 cancer-associated genes using panel testing. Further analyses included 92 cases of pathological stage I NSCLC who did not receive adjuvant chemotherapy. Ridge regression was performed to identify association studies mutational status and postoperative recurrence. These data were then validated using clinical and genetic data from 56 patients in The Cancer Genome Atlas (TCGA).
RESULTS: Mutations in TP53, RAS signaling genes KRAS and HRAS, and EGFR were recurrently detected. Ridge regression analysis relevant to recurrence, as well as survival analysis, performed using data from the TMDU cohort revealed significantly shorter relapse-free survival (RFS) for patients with RAS signaling or TP53 gene mutations than for those without (log-rank test, p = 0.00090). This statistical trend was also suggested in the TCGA cohort (log-rank test, p = 0.10).
CONCLUSION: Mutations in RAS signaling genes and/or TP53 could be useful for the prediction of shorter RFS of patients with stage I NSCLC.

Keywords:   TP53 ; RAS signaling genes; non-small cell lung cancer; pathological stage I

DOI:  https://doi.org/10.1002/cam4.6535