bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2023–11–19
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Exploring the implications of modified advanced lung cancer inflammation index on outcomes in patients with advanced non-small cell lung cancer.
  2. STK11 loss leads to YAP1-mediated transcriptional activation in human KRAS-driven lung adenocarcinoma cell lines.
  3. Circulating tumour cells and PD-L1-positive small extracellular vesicles: the liquid biopsy combination for prognostic information in patients with metastatic non-small cell lung cancer.
  4. IL-17A promotes tumorigenesis and upregulates PD-L1 expression in non-small cell lung cancer.
  5. β‑carotene attenuates muscle wasting in cancer cachexia by regulating myogenesis and muscle atrophy.
  6. First-in-Human Study with preclinical data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors.
  7. Obesity paradox in patients with non-small cell lung cancer undergoing immune checkpoint inhibitor therapy.
  1. Explor Target Antitumor Ther. 2023 ;4(5): 896-911
    Exploring the implications of modified advanced lung cancer inflammation index on outcomes in patients with advanced non-small cell lung cancer.
    Abhishek Mahajan, Devendra Goyal, Ujjwal Agarwal, Vijay Patil, Shreya Shukla, Vanita Noronha, Amit Joshi, Nandini Menon, Kumar Prabhash.
       Aim: Sarcopenia and skeletal muscle density (SMD) have been shown to be both predictive and prognostic marker in oncology. Advanced lung cancer inflammation index (ALI) has been shown to predict overall survival (OS) in small cell lung cancer (SCLC). Computed tomography (CT) enables skeletal muscle to be quantified, whereas body mass index (BMI) cannot accurately reflect body composition. The purpose was to evaluate the prognostic value of modified ALI (mALI) using CT-determined third lumbar vertebra (L3) muscle index beyond original ALI and see the interaction between sarcopenia, SMD, neutrophil-lymphocyte ratio (NLR), ALI and mALI at baseline and post 4 cycles of chemotherapy and their effects on OS and progress free survival (PFS) in patients with advanced non-SCLC (NSCLC).
    Methods: This retrospective study consisted of a total of 285 advanced NSCLC patients. The morphometric parameters such as SMD, skeletal muscle index (SMI) and fat-free mass (FFM) were measured by CT at the L3 vertebra. ALI was defined as BMI × serum albumin/NLR and mALI was defined as SMI × serum albumin/NLR.
    Results: Sarcopenia was observed in over 70% of patients across all BMI categories. Patients having sarcopenia suffered from a higher incidence of chemotherapeutic drug toxicities but this was not found to be statistically significant. Concordance was seen between ALI and mALI in the pre-treatment setting and this was statistically significant. A significant proportion of patients with poor ALI (90.9%), poor pre-chemotherapy mALI (91.3%) and poor post-chemotherapy mALI (89%) had poor NLR and each of them was statistically significant.
    Conclusions: In both univariate and multivariate analyses, this study demonstrated the statistical significance of sarcopenia, SMD, and mALI as predictive factors for OS. Additionally, sarcopenia and SMD were also found to be statistically significant factors in predicting PFS. These biomarkers could potentially help triage patients for active nutritional intervention for better outcomes.
    Keywords:  Sarcopenia; advanced lung cancer inflammation index; advanced non-small cell lung cancer; modified advanced lung cancer inflammation index
    DOI:  https://doi.org/10.37349/etat.2023.00172
  2. Cancer Gene Ther. 2023 Nov 15.
    STK11 loss leads to YAP1-mediated transcriptional activation in human KRAS-driven lung adenocarcinoma cell lines.
    Sean M Lenahan, Hailey M Sarausky, Paula Deming, David J Seward.
      Serine Threonine Kinase 11 (STK11) loss of function (LoF) correlates with anti-PD-1 therapy resistance in patients with KRAS-driven lung adenocarcinoma (LUAD). The molecular mechanisms governing this observation remain unclear and represent a critical outstanding question in the field of lung oncology. As an initial approach to understand this phenomenon, we knocked-out (KO) STK11 in multiple KRAS-driven, STK11-competent human LUAD cell lines and performed whole transcriptome analyses to identify STK11-loss-dependent differential gene expression. Subsequent pathway enrichment studies highlighted activation of the HIPPO/YAP1 signaling axis, along with the induction of numerous tumor-intrinsic cytokines. To validate that YAP1-mediated transcriptional activation occurs in response to STK11 loss, we pursued YAP1 perturbation as a strategy to restore an STK11-competent gene expression profile in STK11-KO LUAD cell lines. Together, our data link STK11 loss with YAP1-mediated transcriptional activation, including the upregulation of immune-evasion promoting cytokines IL-6, CXCL8 and CXCL2. Further, our results raise the intriguing possibility that YAP1 antagonism may represent a therapeutic approach to counter anti-PD-1 therapy resistance in STK11-null, KRAS-driven LUADs by modulating tumor-intrinsic gene expression to promote a "hot" tumor immune microenvironment.
    DOI:  https://doi.org/10.1038/s41417-023-00687-y
  3. Br J Cancer. 2023 Nov 16.
    Circulating tumour cells and PD-L1-positive small extracellular vesicles: the liquid biopsy combination for prognostic information in patients with metastatic non-small cell lung cancer.
    Zahra Eslami-S, Luis Enrique Cortés-Hernández, Léa Sinoquet, Ludovic Gauthier, Valentin Vautrot, Laure Cayrefourcq, Laure Avoscan, William Jacot, Stéphane Pouderoux, Marie Viala, Quentin Dominique Thomas, Pierre-Jean Lamy, Xavier Quantin, Jessica Gobbo, Catherine Alix-Panabières.
       BACKGROUND: Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and extracellular vesicles (EVs) are minimally invasive liquid biopsy biomarkers. This study investigated whether they predict prognosis, alone or in combination, in heterogenous unbiased non-small cell lung cancer (NSCLC) patients.
    METHODS: Plasma samples of 54 advanced NSCLC patients from a prospective clinical trial. CtDNA mutations were identified using the UltraSEEK™ Lung Panel (MassARRAY® technology). PD-L1 expression was assessed in small EVs (sEVs) using an enzyme-linked immunosorbent assay.
    RESULTS: At least one ctDNA mutation was detected in 37% of patients. Mutations were not correlated with overall survival (OS) (HR = 1.1, 95% CI = 0.55; 1.83, P = 0.980) and progression-free survival (PFS) (HR = 1.00, 95% CI = 0.57-1.76, P = 0.991). High PD-L1+ sEV concentration was correlated with OS (HR = 1.14, 95% CI = 1.03-1.26, P = 0.016), but not with PFS (HR = 1.08, 95% CI = 0.99-1.18, P = 0.095). The interaction analysis suggested that PD-L1+ sEV correlation with PFS changed in function of CTC presence/absence (P interaction = 0.036). The combination analysis highlighted worse prognosis for patients with CTCs and high PD-L1+ sEV concentration (HR = 7.65, 95% CI = 3.11-18.83, P < 0.001). The mutational statuses of ctDNA and tumour tissue were significantly correlated (P = 0.0001).
    CONCLUSION: CTCs and high PD-L1+ sEV concentration correlated with PFS and OS, but not ctDNA mutations. Their combined analysis may help to identify patients with worse OS.
    TRIAL REGISTRATION: NCT02866149, Registered 01 June 2015, https://clinicaltrials.gov/ct2/show/study/NCT02866149 .
    DOI:  https://doi.org/10.1038/s41416-023-02491-9
  4. J Transl Med. 2023 Nov 17. 21(1): 828
    IL-17A promotes tumorigenesis and upregulates PD-L1 expression in non-small cell lung cancer.
    Hua Liao, Xiaodan Chang, Lin Gao, Cuiping Ye, Yujie Qiao, Lingyan Xie, Jie Lin, Shaoxi Cai, Hangming Dong.
       BACKGROUND: The tumor microenvironment plays a key role in non-small cell lung cancer (NSCLC) development and also influences the effective response to immunotherapy. The pro-inflammatory factor interleukin-17A mediates important immune responses in the tumor microenvironment. In this study, the potential role and mechanisms of IL-17A in NSCLC were investigated.
    METHODS: We detected IL-17A by immunohistochemistry (IHC) in 39 NSCLC patients. Its expression was correlated with the programmed cell death-ligand1 (PD-L1). IL-17A knockdown and overexpression in A549 and SPC-A-1 cell models were constructed. The function of IL-17A was examined in vitro by wound healing, migration, invasion, plate colony formation and T cell killing assay. Western blot analysis, immunofluorescence assay and IHC were performed to investigate the regulation effects of IL-17A on autophagy in A549 and SPC-A-1. The effect of IL-17A on ROS/Nrf2/p62 signaling pathway was detected. Subcutaneous tumor models were established to examine the tumor-promoting effect of IL-17A in vivo and its effect on immunotherapy.
    RESULTS: We found a prevalent expression of IL-17A in NSCLC tumor tissues and it was positively correlated with PD-L1 expression (r = 0.6121, p < 0.0001). In vitro, IL-17A promotes lung cancer cell migration, invasion and colony formation ability. Moreover, IL-17A upregulated N-cadherin, Twist, and Snail, and downregulated E-cadherin in NSCLC cells. IL-17A enhanced cell survival in the T cell killing assay. Mechanistically, IL-17A induced ROS production and increased Nrf2 and p62 expression, thereby inhibiting autophagy and reducing PD-L1 degradation. In vivo experiments, anti-IL-17A monoclonal antibody alone slowed the growth of subcutaneous tumors in mice. When combined with anti-PD-L1 monoclonal antibody, tumor tissue expression of PD-L1 was reduced and the therapeutic effect was diminished.
    CONCLUSION: We found that IL-17A promoted NSCLC progression and inhibited autophagy through the ROS/Nrf2/p62 pathway leading to increased PD-L1 expression in cancer cells. Modulation of IL-17A may affect the therapeutic efficacy of immunotherapy.
    Keywords:  Autophagy; Immunotherapy; Interleukin-17A; NSCLC; PD-L1
    DOI:  https://doi.org/10.1186/s12967-023-04365-3
  5. Oncol Rep. 2024 Jan;pii: 9. [Epub ahead of print]51(1):
    β‑carotene attenuates muscle wasting in cancer cachexia by regulating myogenesis and muscle atrophy.
    Yerin Kim, Yeonsoo Oh, Yoo Sun Kim, Jae-Ho Shin, Yeon Su Lee, Yuri Kim.
      Cancer cachexia is a metabolic disease involving multiple organs, which is accompanied by the depletion of muscle tissue and is associated with ~20% of cancer‑related deaths. Muscle wasting is a critical factor in cancer cachexia. β‑carotene (BC) has been shown to increase muscle mass and hypertrophy in healthy mice. However, its effects on muscle tissue dysregulation in cancer cachexia have yet to be studied. In the present study, 5‑week‑old male C57BL/6J mice were injected with 1x106 Lewis lung carcinoma (LLC) cells to induce cancer cachexia; then the mice were administered BC (4 or 8 mg/kg) for 22 days to assess its effects on muscle atrophy in the gastrocnemius muscles. The effects of BC on inflammatory cytokines, myogenesis and muscle atrophy were evaluated using C2C12 myotubes treated with LLC‑conditioned media. BC supplementation significantly suppressed tumor growth, inflammatory cytokines, and hepatic gluconeogenesis in the LLC‑induced cancer cachexia mouse model, while also improving muscle weight and grip strength. These effects are considered to be mediated by the PI3K/Akt pathway and through regulation of muscle atrophy. Moreover, BC treatment was associated with the recovery of LLC‑conditioned media‑induced muscle differentiation deficits and muscle atrophy in C2C12 myotubes. These findings indicate BC as a potential novel therapeutic agent for cancer cachexia.
    Keywords:  cancer cachexia; muscle atrophy; muscle wasting; myogenesis; β‑carotene
    DOI:  https://doi.org/10.3892/or.2023.8668
  6. Clin Cancer Res. 2023 Nov 16.
    First-in-Human Study with preclinical data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors.
    Nehal J Lakhani, Drew Rasco, Hengbang Wang, Lichuang Men, Eric Liang, Tommy Fu, Mary C Collins, Ping Min, Yan Yin, Matthew S Davids, Dajun Yang, Yifan Zhai.
       PURPOSE: BCL-xL regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Employing an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA).
    EXPERIMENTAL DESIGN: Cell line-derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint.
    RESULTS: Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell- based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein MCL-1. Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule.
    CONCLUSIONS: Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-1525
  7. J Cachexia Sarcopenia Muscle. 2023 Nov 14.
    Obesity paradox in patients with non-small cell lung cancer undergoing immune checkpoint inhibitor therapy.
    Ji Hyun Lee, Danbee Kang, Jin Seok Ahn, Eliseo Guallar, Juhee Cho, Ho Yun Lee.
       BACKGROUND: The obesity paradox in patients with advanced non-small cell lung cancer receiving immune checkpoint inhibitor therapy has been observed, but its underlying mechanism is not fully understood. We aimed to investigate whether body composition affects the prognostic impact of obesity, as determined by body mass index (BMI), on survival.
    METHODS: This retrospective study evaluated the data collected from Asian patients who were treated with immune checkpoint inhibitors for advanced non-small cell lung cancer between October 2015 and October 2021. We used abdominal cross-sectional imaging to calculate the skeletal muscle and visceral fat indices (cm2 /m2 ) by dividing the cross-sectional areas of the skeletal muscle and visceral fat by the height squared. Cox proportional-hazards regression was performed to determine the correlation between BMI according to the Asia-Pacific classification, body composition metrics and overall survival.
    RESULTS: We analysed the data of 820 patients (630 men and 190 women, with a mean age of 64.3 years [standard deviation: 10.4 years]) and observed 572 (69.8%) deaths with the 1-year mortality rate of 0.58 (95% confidence interval, 0.55-0.62). Obese BMI was associated with longer overall survival, independent of clinical covariates (hazard ratio, 0.64; 95% confidence interval: 0.52-0.80). The prognostic value of obese BMI remained after additional adjustments for skeletal muscle index (hazard ratio, 0.68; 95% confidence interval, 0.53-0.87) or visceral fat index (hazard ratio, 0.54; 95% confidence interval: 0.41-0.70). No association was observed between sex and the impact of BMI on overall survival (P-value for interaction >0.05).
    CONCLUSIONS: In Asian patients with advanced non-small cell lung cancer who received immune checkpoint inhibitors, obese BMI was associated with favourable overall survival independent of skeletal muscle or visceral fat mass.
    Keywords:  Immune checkpoint inhibitors; Immunotherapy; Lung neoplasms; Non-small cell lung cancer; Tumour biomarkers
    DOI:  https://doi.org/10.1002/jcsm.13367
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