bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2025–01–26
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The Impacts of Active and Inactive Ghrelin on Cachexia and Immune Checkpoint Inhibitor Monotherapy in Patients with Non-small Cell Lung Cancer.
  2. Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer.
  3. Endoplasmic reticulum stress-MMRN1 positive feedback contributes to cisplatin resistance in small cell lung cancer.
  4. Prognostic value of serum cholinesterase and 18F-FDG PET/CT-derived metabolic parameters in non-small cell lung cancer patients: a retrospective cohort study.
  5. The impact of KRAS mutations on the tumour microenvironment and treatment response in non-small cell lung cancer.
  6. Plasma S100A8/A9 level predicts response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.
  7. In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in KRASG12C--mutant non-small cell lung cancer.
  8. KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors.
  9. The role of PCBP1 in carbon ion-induced ferroptosis and inhibition of lung adenocarcinoma proliferation.
  10. Inhibition of the anti-apoptotic protein BCL2 in EML4-ALK cell models as a second proposed therapeutic target for non-small cell lung cancer.
  1. Chemotherapy. 2025 Jan 22. 1-15
    The Impacts of Active and Inactive Ghrelin on Cachexia and Immune Checkpoint Inhibitor Monotherapy in Patients with Non-small Cell Lung Cancer.
    Daiki Murata, Koichi Azuma, Yuuya Nishii, Kenta Murotani, Goushi Matama, Akihiko Kawahara, Takaaki Tokito, Tetsuro Sasada, Tomoaki Hoshino.
       BACKGROUND: Identifying the underlying mechanisms of immune checkpoint inhibitor resistance in patients with cachexia is a current challenge. Ghrelin is a peptide hormone that plays an important role in the metabolism of patients with cancer cachexia. Despite the importance of ghrelin in cancer cachexia, most previous studies on the subject have not distinguished between the forms of ghrelin.
    MATERIAL AND METHODS: We retrospectively screened patients with advanced or recurrent non-small cell lung cancer receiving PD-1/PD-L1 inhibitor monotherapy. Active and inactive ghrelin levels were measured in 100 patients with available plasma samples at immune checkpoint inhibitor initiation. Cancer cachexia was defined as weight loss of at least 5% during the past 6 months or weight loss of at least 2% with a BMI < 20. We analyzed the associations of the active and inactive ghrelin levels and active-to-inactive ghrelin ratio (AIR) with cancer cachexia. The prognostic impact of the active and inactive ghrelin levels and AIR were also analyzed.
    RESULTS: Among 100 patients, 35 were diagnosed with cancer cachexia. The active ghrelin level and AIR were significantly associated with cancer cachexia, whereas the inactive ghrelin level was not. The active and inactive ghrelin levels and AIR were not associated with patient prognosis.
    CONCLUSIONS: The active ghrelin level and AIR were associated with cancer cachexia but not with patient prognosis. The function of the active and inactive forms of ghrelin may differ in cancer patients. The form of ghrelin should be clearly mentioned in relevant studies on cancer cachexia.
    DOI:  https://doi.org/10.1159/000543425
  2. Transl Lung Cancer Res. 2024 Dec 31. 13(12): 3718-3730
    Emerging insights into STK11, KEAP1 and KRAS mutations: implications for immunotherapy in patients with advanced non-small cell lung cancer.
    Magdalena Knetki-Wróblewska, Kamila Wojas-Krawczyk, Paweł Krawczyk, Maciej Krzakowski.
      Immune checkpoint inhibitors (ICIs) have become an established treatment option for patients with advanced non-small cell lung cancer (NSCLC). However, the efficacy of single-agent immunotherapy as well as in combination with chemotherapy seems to be dependent on the presence of molecular abnormalities in some genes-serine/threonine kinase 11 (STK11), Kelch-like ECH-associated protein 1 (KEAP1) and Kirsten rat sarcoma viral oncogene homolog (KRAS) among them. The KEAP1 gene is a critical regulator of the cellular response to oxidative stress and electrophilic stress, thus playing a pivotal role in maintaining cellular homeostasis. The STK11 gene encodes a serine/threonine kinase (STK11) involved the regulation of cell growth, polarity, motility, differentiation and cell metabolism. The STK11 gene mutations are often associated with an immunologically "cold" tumour microenvironment. The co-occurrence of STK11 or KEAP1 abnormalities with the KRAS mutation changes the composition of the tumour microenvironment as compared when presented alone. The current data, based on retrospective analyses of clinical trials, indicate that the co-existence of STK11 and KEAP1 genes mutations with the KRAS gene mutations have negative impact on the prognosis, regardless of treatment methods, in patients with advanced NSCLC. However, this group of patients should not be omitted because they constitute a significant percentage of advanced NSCLC patients. Immunotherapy focused on two ICIs [anti-programmed death 1 (PD-1)/anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)] combined with chemotherapy, may be more effective than immunotherapy or chemotherapy alone in this group of patients. Confirmation of this thesis can be found in the results of available clinical studies. Here, we summarize the theoretical justification as well as the results of clinical trials for combining immunotherapy in patients with STK11-, KEAP1- and KRAS-mutated genes. There is certainly a need to create a prospective clinical trial to assess the effectiveness of combined immunotherapy in the discussed group of patients.
    Keywords:  Kelch-like ECH-associated protein 1 (KEAP1); Kirsten rat sarcoma viral oncogene homolog (KRAS); immune checkpoint inhibitors (ICIs); serine/threonine kinase 11 (STK11)
    DOI:  https://doi.org/10.21037/tlcr-24-552
  3. J Thorac Dis. 2024 Dec 31. 16(12): 8363-8378
    Endoplasmic reticulum stress-MMRN1 positive feedback contributes to cisplatin resistance in small cell lung cancer.
    Mingxin Liu, Peihong Hu, Bo Tang, Qi Yang, Run Xiang, Yiqiang Liu, Juan Li, Binghuo Wu, Hong Wu, Bo Tian, Chuan Xu, Qiang Li.
       Background: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and presents early metastasis and poor prognosis. Chemotherapy with cisplatin (CDDP) remains one of the standards of care in first-line treatment. However, the emergence of acquired resistance to CDDP causes disease progression and cancer recurrence. A comprehensive understanding of the CDDP-resistant mechanisms aids in defining accurate biomarkers and developing potential strategies.
    Methods: The liquid chromatograph mass spectrometer (LC-MS/MS) was conducted to analyze the differential exosomal proteins from plasma samples of SCLC patients with non-treatment or resistance to CDDP. The online RNA-seq data with clinicopathological information on SCLC patients were downloaded from the Gene Expression Omnibus (GEO) database for further prognostic analysis. The SCLC cell line model of acquired CDDP resistance was established to investigate the role of platelet protein multimerin-1 (MMRN1) in CDDP resistance.
    Results: MMRN1 was increased in CDDP-resistant SCLC patients and cell line models. Reduction of MMRN1 recovered the sensitivity to CDDP while overexpression of MMRN1 conferred CDDP resistance. The CDDP-resistant SCLC cells disseminated resistant to the CDDP-sensitive SCLC cells via the exosomal MMRN1. Additionally, CDDP treatment induces endoplasmic reticulum (ER) stress and subsequent upregulation of MMRN1. Increasing MMRN1 interacted with binding immunoglobulin protein (BiP) in the ER, maintaining the ER stress in SCLC cells.
    Conclusions: The present study identified exosomal MMRN1 as a potential biomarker for CDDP resistance in SCLC. MMRN1 sustains ER stress via interaction with BiP and subsequently facilitates CDDP resistance, which might be a promising therapeutic target to overcome CDDP resistance.
    Keywords:  Small cell lung cancer (SCLC); binding immunoglobulin protein (BiP); cisplatin resistance; endoplasmic reticulum stress (ER stress); multimerin-1 (MMRN1)
    DOI:  https://doi.org/10.21037/jtd-24-1477
  4. Nucl Med Commun. 2025 Jan 21.
    Prognostic value of serum cholinesterase and 18F-FDG PET/CT-derived metabolic parameters in non-small cell lung cancer patients: a retrospective cohort study.
    Na Hu, Gang Yan, Maowen Tang, Shengmei Yuan, Xing Xia, Pinggui Lei.
       PURPOSE: The primary objective of this study was to explore the prognostic significance of serum cholinesterase (CHE) and metabolic parameters obtained from 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) scans in patients with nonsmall cell lung cancer (NSCLC).
    METHODS: A retrospective observational cohort study was conducted with 202 NSCLC patients. Serum CHE was evaluated alongside metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from PET/CT scans. The correlation between these parameters and overall survival (OS) was analyzed using log-rank tests, as well as univariate and multivariate Cox regression analyses. A nomogram prediction model was developed and assessed using time-dependent receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA).
    RESULTS: High MTV (≥16) and TLG (≥108) were found to be significantly correlated with worse OS outcomes (both P < 0.001), whereas lower CHE levels (<6818) were associated with worse OS (P = 0.002). A multivariate analysis revealed that MTV, TLG, serum CHE, and the presence of distant metastasis were independent prognostic factors for OS. The nomogram prediction model, incorporating these variables, exhibited strong predictive performance, as indicated by area under the curve values of 0.826, 0.796, and 0.845 for 1-, 3-, and 5-year OS predictions, respectively. Calibration curves demonstrated good concordance between predicted and observed survival rates, and DCA confirmed clinical relevance.
    CONCLUSIONS: Serum CHE and 18F-FDG PET/CT metabolic parameters may serve as important prognostic indicators for patients with NSCLC. The integration of these factors into a nomogram prediction model can assist in clinical decision-making and patient risk stratification.
    DOI:  https://doi.org/10.1097/MNM.0000000000001952
  5. Pol J Pathol. 2024 ;pii: 55436. [Epub ahead of print]75(4): 353-361
    The impact of KRAS mutations on the tumour microenvironment and treatment response in non-small cell lung cancer.
    Guomin Gu, Chunling Liu, Yan Yang, Yan Zhao, Xiaodan Zhu, Gang Sun.
      Mutations in the KRAS gene in non-small cell lung cancer (NSCLC) are common drivers. Gene expression and mutation data of NSCLC were collected from the TCGA dataset. DEGs between KRAS mutations and wild type were identified, and enrichment analysis was performed. The differences in immune cell infiltration between the 2 groups were evaluated using ssGSEA, and TIDE scoring, immune checkpoint therapy sensitivity, and drug treatment sensitivity analysis were performed. The expression of PD-L1 and CTLA-4 in tumour tissues was detected by western blot. CD8+PD-1 and CD8+CTLA-4 cells were detected by flow cytometry. The frequencies of KRAS-G12C, KRAS-G12V, and KRAS-G12D mutations were the highest. A total of 1323 DEGs were predominantly enriched in the PI3K-Akt signalling pathway, cell adhesion molecules, and metabolism of xenobiotics by cytochrome P450. Additionally, most immune cell infiltration levels in KRAS mutations were lower than in KRAS wild type. Sensitivity to immune checkpoint inhibitors and drug treatments increased in KRAS mutations. Western blot revealed significantly higher expressions of PD-L1 and CTLA-4 in KRAS mutations compared to KRAS wild type. The infiltration of CD8+PD-1+ T cells and CD8+CTLA-4+ T cells was higher in KRAS mutations than in KRAS wild type. KRAS-G12C, KRAS-G12V, and KRAS-G12D mutations may enhance NSCLC drug resistance through immunosuppression.
    Keywords:   KRAS; immune checkpoint; treatment response; non-small cell lung cancer
    DOI:  https://doi.org/10.5114/pjp.2024.146544
  6. Sci Rep. 2025 Jan 20. 15(1): 2577
    Plasma S100A8/A9 level predicts response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.
    Tadahiro Kuribayashi, Rie Kinoshita, Kiichiro Ninomiya, Go Makimoto, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura, Shinichi Toyooka, Masakiyo Sakaguchi, Kadoaki Ohashi.
      Blood-based predictive markers for the efficacy of immune checkpoint inhibitors (ICIs) have not yet been established. We investigated the association of the plasma level of S100A8/A9 with the efficacy of immunotherapy. We evaluated patients with unresectable stage III/IV or recurrent non-small cell lung cancer (NSCLC) who were treated with ICIs at Okayama University Hospital. The pre-treatment plasma levels of S100A8/A9 were analyzed. Eighty-one eligible patients were included (median age, 69 years). Sixty-two patients were men, 54 had adenocarcinoma, 74 had performance status (PS) 0-1, and 47 received ICIs as first-line treatment. The median time to treatment failure (TTF) for ICIs was 5.7 months, and the median overall survival (OS) was 19.6 months. The TTF and OS were worse in patients with high plasma S100A8/A9 levels (≥ 2.475 µg/mL) (median TTF: 4.3 vs. 8.5 months, p = 0.009; median OS: 15.4 vs. 38.0 months, p = 0.001). Multivariate analysis revealed that PS ≥ 2, liver metastasis, and high plasma S100A8/A9 levels were significantly associated with short TTF and OS. In conclusion, plasma S100A8/A9 level may have a limited effect on ICI therapy for NSCLC.
    Keywords:  Immune checkpoint inhibitors; Lung cancer; S100A8/A9
    DOI:  https://doi.org/10.1038/s41598-025-87232-z
  7. Clin Cancer Res. 2025 Jan 21.
    In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in KRASG12C--mutant non-small cell lung cancer.
    Ryoji Kato, Hitendra S Solanki, Hilal Ozakinci, Bina Desai, Harika Gundlapalli, Yu Chi Yang, Ida Aronchik, Mallika Singh, Joseph Johnson, Andriy Marusyk, Theresa A Boyle, Eric B Haura.
       PURPOSE: Therapeutic efficacy of KRASG12C(OFF) inhibitors (KRASG12Ci) in KRASG12C-mutant non-small cell lung cancer (NSCLC) varies widely. The activation status of RAS signaling in tumors with KRASG12C mutation remains unclear, as its ability to cycle between the active GTP-bound and inactive GDP-bound states may influence downstream pathway activation and therapeutic responses. We hypothesized that the interaction between RAS and its downstream effector RAF in tumors may serve as indicators of RAS activity, rendering NSCLC tumors with a high degree of RAS engagement and downstream effects more responsive to KRASG12Ci compared to tumors with lower RAS---RAF interaction.
    EXPERIMENTAL DESIGN: We developed a method for measuring in situ RAS binding to RAF in cancer samples using proximity ligation assays (PLAs) designed to detect panRAS-CRAF interactions.
    RESULTS: The panRAS-CRAF PLA signal correlated with levels of both RAS-GTP and phosphorylated ERK protein, suggesting that this assay can effectively assess active RAS signaling. We found that elevated panRAS-CRAF PLA signals were associated with increased sensitivity to KRASG12Ci in KRASG12C-mutant NSCLC cell lines, xenograft models, and patient samples. Applying a similar PLA approach to measure the interactions between EGFR and its adaptor protein GRB2 as a surrogate for EGFR activity, we found no relationship between EGFR activity and response to KRASG12Ci in the same samples.
    CONCLUSIONS: Our study highlights the importance of evaluating in situ RAS-RAF interactions as a potential predictive biomarker for identifying NSCLC patients most likely to benefit from KRASG12Ci. The PLA developed for quantifying these interactions represents a valuable tool for guiding treatment strategies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3714
  8. J Transl Med. 2025 Jan 17. 23(1): 82
    KEAP1 mutations as key crucial prognostic biomarkers for resistance to KRAS-G12C inhibitors.
    Linyan Tian, Chengming Liu, Sufei Zheng, Huiyang Shi, Fang Wei, Wenxin Jiang, Yucheng Dong, Haiyan Xu, Enzhi Yin, Nan Sun, Jie He, Yan Wang.
       BACKGROUND: KRAS-G12C inhibitors mark a notable advancement in targeted cancer therapies, yet identifying predictive biomarkers for treatment efficacy and resistance remains essential for optimizing clinical outcomes.
    METHODS: This systematic meta-analysis synthesized studies available through September 2024 across PubMed, Cochrane Library, SpringerLink, and Embase. Using CRISPR/Cas9 technology, this study generated cells with KEAP1 and STK11 knockouts, and utilized lentiviral vectors to overexpress PD-L1. Cellular sensitivity to KRAS-G12C inhibitors-AMG510, MRTX849, and JAB-21822-was evaluated through CCK-8 assays. Comprehensive bioinformatics analyses on stably transfected cell lines were conducted to elucidate pathways mediating resistance.
    RESULTS: Analysis of 13 studies involving 1132 patients highlighted the significant efficacy of KRAS-G12C inhibitor monotherapy, particularly among elderly and female patients. Treatment response was notably affected by liver and brain metastases, with KEAP1 mutations identified as a primary negative prognostic factor, closely associated with early resistance to treatment. Validation studies in NCI-H358 cells showed a marked increase in IC50 values for AMG510, MRTX849, and JAB-21822 after KEAP1 knockout (P < 0.0001), with IC50 values rising from 27.78 nm, 116.9 nm, and 118.7 nm in controls, respectively. Comparative analysis of differentially expressed genes in KEAP1 knockout cells versus controls, utilizing GO, KEGG, and Reactome pathway analyses, revealed substantial enrichment in pathways linked to extracellular matrix organization and cell adhesion processes. Although STK11 mutations and heightened PD-L1 expression indicated a trend toward poorer outcomes, these correlations lacked statistical significance.
    CONCLUSION: This research affirms KRAS-G12C inhibitors as promising treatments, especially for certain patient subgroups, and underscores KEAP1 mutations as key biomarkers for resistance. The findings highlight the urgent need for alternative therapeutic approaches in KEAP1-mutant patients and emphasize the role of molecular profiling in tailored treatment strategies.
    Keywords:  Biomarkers; Drug resistance; KEAP1 mutations; KRAS-G12C inhibitors; Targeted therapy
    DOI:  https://doi.org/10.1186/s12967-025-06089-y
  9. Front Public Health. 2024 ;12 1496439
    The role of PCBP1 in carbon ion-induced ferroptosis and inhibition of lung adenocarcinoma proliferation.
    Zhenchao Kang, Zihan Fu, Xuejiao Tian, Yichao Geng, Qiuning Zhang, Yanli Liu, Xinhua Wang, Hongtao Luo, Zhen Yang.
       Objective: To investigate the role of PCBP1 in the inhibition of lung adenocarcinoma proliferation by carbon irradiation.
    Methods: A549 cells were irradiated with different doses of carbon ions to observe clonal survival and detect changes in cell proliferation. Whole transcriptome sequencing and the Illumina platform were used to analyze the differentially expressed genes in A549 cells after carbon ion irradiation. The relationship between the expression levels of PCBP1, ACSL4, and ALOX15 and survival was analyzed by combining data from the UCSC database and the Kaplan-Meier Plotter public platform. Additionally, the knockdown of the poly (rC)-binding protein 1 (PCBP1) gene using siRNA techniques was employed to further investigate the relationship between the expression levels of PCBP1 and ALOX15. To investigate the relationship between ALOX15 expression and survival, we assessed changes in key indicators of ferroptosis (mitochondrial morphology, ROS, MDA, and divalent iron) in A549 cells after knocking down the PCBP1 gene using siRNA technology. Additionally, the expressions of PCBP1, ACSL4, and ALOX15 in different groups were further analyzed through RT-PCR and Western blot techniques. The differential expression of PCBP1, ACSL4, and ALOX15 in NSCLC tissues was found to correlate with clinical prognosis for survival.
    Results: Carbon ions significantly inhibited the proliferation of A549 cells, and 5.16 Gy carbon ions significantly induced the expression of differentially expressed genes in these cells. Additionally, carbon ions inhibited the expression of PCBP1, which led to alterations in mitochondrial morphology in lung adenocarcinoma cells. This was associated with a significant increase in the levels of ROS, MDA, and Fe2+. Furthermore, low expression of PCBP1 promoted ferroptosis by increasing the expression of ACSL4 and ALOX15.
    Conclusion: Carbon ions decreased the expression of PCBP1 in A549 cells, and low expression of PCBP1 inhibited tumor proliferation by promoting ferroptosis.
    Keywords:  PCBP1; carbon ion; ferroptosis; lung adenocarcinoma; proliferation
    DOI:  https://doi.org/10.3389/fpubh.2024.1496439
  10. PLoS One. 2025 ;20(1): e0308747
    Inhibition of the anti-apoptotic protein BCL2 in EML4-ALK cell models as a second proposed therapeutic target for non-small cell lung cancer.
    Richard Junior Zapata Dongo, Diletta Fontana, Luca Mologni, Juan Enrique Faya Castillo, Stefany Fiorella Infante Varillas.
      The anaplastic lymphoma kinase (ALK) oncoprotein plays a crucial role in non-small cell lung cancer (NSCLC) by activating signaling pathways involved in cell proliferation and survival through constitutive phosphorylation. While first-line crizotinib can regulate phosphorylation, mutations in the ALK gene can lead to resistance against ALK inhibitors (ALKi) such as ceritinib and alectinib. On the other hand, overexpression of BCL2, a protein involved in cell death regulation, has been observed in NSCLC and is considered a potential therapeutic target. In this study, we propose to inhibit BCL2 as a secondary therapeutic target in EML4-ALK cell models to overcome resistance caused by ALK mutations. Four Ba/F3 EML4-ALK cell models (WT, C1156Y, L1196M, and G1202R) generated by site-directed mutagenesis exhibited varying levels of BCL2 expression. Both the WT and G1202R models showed overexpression of BCL2, while C1156Y and L1196M models approached baseline levels. We treated these cells with ABT-199, a selective BCL2 inhibitor, and found that models with high BCL2 expression exhibited resistance, while those with lower expression showed sensitivity to BCL2 inhibition. In addition, our analysis using bioinformatics indicated that ABT-199 not only targets BCL2 but also binds to the active site of all ALK mutants, it was contrasted by in vitro ALK kinase activity inhibition by ABT-199 (5.5 μM). This interaction was further supported by a significant decrease of ALK phosphorylation in single and combination treatment with 300nM ABT-199. Finally, when ABT-199 was combined with ALKi, we observed a wide range of synergistic effects in the WT and G1202R cell models, while the C1156Y and L1196M models showed limited synergy. In conclusion, our findings indicate that BCL2 targeting with ABT-199, in combination with ALKi, can significantly reduce tumor cell survival in Ba/F3 EML4-ALK cell models.
    DOI:  https://doi.org/10.1371/journal.pone.0308747
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒27 at 16:34.