bims-meluca 2023-05-28 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–05–28
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small-cell lung cancer patients.
Metabolic heterogeneity in TNBCs: A potential determinant of therapeutic efficacy of 2-deoxyglucose and metformin combinatory therapy.
Value of chemotherapy post immunotherapy in stage IV non-small cell lung cancer (NSCLC).
Prognostic Value of CXCL12 in Non-Small Cell Lung Cancer Patients Undergoing Tumor Resection.
The impact of cancer cachexia on gut microbiota composition and short-chain fatty acid metabolism in a murine model.
Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma.
Mutation of TP53 confers ferroptosis resistance in lung cancer through the FOXM1/MEF2C axis.

bioRxiv. 2023 May 09. pii: 2023.05.08.539908. [Epub ahead of print]

Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.

Lara Ibrahim, Caroline Stanton, Kayla Nutsch, Thu Nguyen, Chloris Li-Ma, Yeonjin Ko, Gabriel C Lander, R Luke Wiseman, Michael J Bollong.

Crosstalk between metabolism and stress-responsive signaling is essential to maintaining cellular homeostasis. One way this crosstalk is achieved is through the covalent modification of proteins by endogenous, reactive metabolites that regulate the activity of key stress-responsive transcription factors such as NRF2. Several metabolites including methylglyoxal, glyceraldehyde 3-phosphate, fumarate, and itaconate covalently modify sensor cysteines of the NRF2 regulatory protein KEAP1, resulting in stabilization of NRF2 and activation of its cytoprotective transcriptional program. Here, we employed a shRNA-based screen targeting the enzymes of central carbon metabolism to identify additional regulatory nodes bridging metabolic pathways to NRF2 activation. We found that succinic anhydride, increased by genetic depletion of the TCA cycle enzyme succinyl-CoA synthetase or by direct administration, results in N-succinylation of lysine 131 of KEAP1 to activate NRF2 transcriptional signaling. This study identifies KEAP1 as capable of sensing reactive metabolites not only by several cysteine residues but also by a conserved lysine residue, indicating its potential to sense an expanded repertoire of reactive metabolic messengers.

DOI: https://doi.org/10.1101/2023.05.08.539908
Cancer Med. 2023 May 21.

Impact of the pretreatment prognostic nutritional index on the survival after first-line immunotherapy in non-small-cell lung cancer patients.

Yuka Oku, Gouji Toyokawa, Sho Wakasu, Fumihiko Kinoshita, Shinkichi Takamori, Kenji Watanabe, Naoki Haratake, Taichi Nagano, Keisuke Kosai, Kazuki Takada, Airi Fujimoto, Kodo Higashijima, Yoshimasa Shiraishi, Kentaro Tanaka, Hiroaki Takeoka, Masaki Okamoto, Takanori Yamashita, Mototsugu Shimokawa, Fumihiro Shoji, Koji Yamazaki, Tatsuro Okamoto, Takashi Seto, Hitoshi Ueda, Sadanori Takeo, Naoki Nakashima, Isamu Okamoto, Tomoyoshi Takenaka, Tomoharu Yoshizumi.

   BACKGROUND: Immunotherapy has become a standard-of-care for patients with non-small-cell lung cancer (NSCLC). Although several biomarkers, such as programmed cell death-1, have been shown to be useful in selecting patients likely to benefit from immune checkpoint inhibitors (ICIs), more useful and reliable ones should be investigated. The prognostic nutritional index (PNI) is a marker of the immune and nutritional status of the host, and is derived from serum albumin level and peripheral lymphocyte count. Although several groups reported its prognostic role in patients with NSCLC receiving a single ICI, there exist no reports which have demonstrated its role in the first-line ICI combined with or without chemotherapy.
MATERIALS AND METHODS: Two-hundred and eighteen patients with NSCLC were included in the current study and received pembrolizumab alone or chemoimmunotherapy as the first-line therapy. Cutoff value of the pretreatment PNI was set as 42.17.
RESULTS: Among 218 patients, 123 (56.4%) had a high PNI (≥42.17), while 95 (43.6%) had a low PNI (<42.17). A significant association was observed between the PNI and both the progression-free survival (PFS; hazard ratio [HR] = 0.67, 95% confidence interval [CI]: 0.51-0.88, p = 0.0021) and overall survival (OS; HR = 0.46, 95% CI: 0.32-0.67, p < 0.0001) in the entire population, respectively. The multivariate analysis identified the pretreatment PNI as an independent prognosticator for the PFS (p = 0.0011) and OS (p < 0.0001), and in patients receiving either pembrolizumab alone or chemoimmunotherapy, the pretreatment PNI remained an independent prognostic factor for the OS (p = 0.0270 and 0.0006, respectively).
CONCLUSION: The PNI might help clinicians appropriately identifying patients with better treatment outcomes when receiving first-line ICI therapy.

Keywords:  chemoimmunotherapy; first-line immunotherapy; monotherapy; non-small-cell lung cancer; prognostic nutritional index

DOI:  https://doi.org/10.1002/cam4.6110
Biomed Pharmacother. 2023 May 22. pii: S0753-3322(23)00701-1. [Epub ahead of print]164 114911

Metabolic heterogeneity in TNBCs: A potential determinant of therapeutic efficacy of 2-deoxyglucose and metformin combinatory therapy.

Samson Mathews Samuel, Elizabeth Varghese, Noothan Jyothi Satheesh, Chris R Triggle, Dietrich Büsselberg.

  Breast cancers (BCs) remain the leading cause of cancer-related deaths among women worldwide. Among the different types of BCs, treating the highly aggressive, invasive, and metastatic triple-negative BCs (TNBCs) that do not respond to hormonal/human epidermal growth factor receptor 2 (HER2) targeted interventions since they lack ER/PR/HER2 receptors remains challenging. While almost all BCs depend on glucose metabolism for their proliferation and survival, studies indicate that TNBCs are highly dependent on glucose metabolism compared to non-TNBC malignancies. Hence, limiting/inhibiting glucose metabolism in TNBCs should curb cell proliferation and tumor growth. Previous reports, including ours, have shown the efficacy of metformin, the most widely prescribed antidiabetic drug, in reducing cell proliferation and growth in MDA-MB-231 and MDA-MB-468 TNBC cells. In the current study, we investigated and compared the anticancer effects of either metformin (2 mM) in glucose-starved or 2-deoxyglucose (10 mM; glycolytic inhibitor; 2DG) exposed MDA-MB-231 and MDA-MB-468 TNBC cells. Assays for cell proliferation, rate of glycolysis, cell viability, and cell-cycle analysis were performed. The status of proteins of the mTOR pathway was assessed by Western blot analysis. Metformin treatment in glucose-starved and 2DG (10 mM) exposed TNBC cells inhibited the mTOR pathway compared to non-treated glucose-starved cells or 2DG/metformin alone treated controls. Cell proliferation is also significantly reduced under these combination treatment conditions. The results indicate that combining a glycolytic inhibitor and metformin could prove an efficient therapeutic approach for treating TNBCs, albeit the efficacy of the combination treatment may depend on metabolic heterogeneity across various subtypes of TNBCs.

Keywords:  Cancer; Diabetes; Hyperglycemia; Metformin; Triple negative breast cancers (TNBCs); Tumor metabolism

DOI:  https://doi.org/10.1016/j.biopha.2023.114911
Oncotarget. 2023 May 26. 14 517-525

Value of chemotherapy post immunotherapy in stage IV non-small cell lung cancer (NSCLC).

Hazem I Assi, Maroun Bou Zerdan, Mohammad Hodroj, Makram Khoury, Nour Sabiha Naji, Ghid Amhaz, Reine Abou Zeidane, Fadi El Karak.

   BACKGROUND: Lung cancer is the number one cause of mortality among all types of cancer worldwide. Its treatment landscape has shifted from the classic chemotherapy alone to newer regimens based on the discovery of new immunotherapy and targeted therapy drugs. However, chemotherapy is still an option for treatment of advanced non-small cell lung cancer (NSCLC) after progression on immunotherapy alone or in combination with first-line chemotherapy.
METHODS: This is a retrospective study based on chart review of patients diagnosed with advanced NSCLC cases who received Docetaxel as second or third line after being treated by immunotherapy and/or chemotherapy in previous lines. The data was collected from the medical records of physicians' clinics in three different hospital centers in Lebanon over the period of 5 years from July 2015 until December 2020. February 2021 was data analysis cut off time. The main aim was to assess the role of Docetaxel post-chemoimmunotherapy for patients with diagnosed NSCLC.
RESULTS: A total of 21 patients were included in this study. The majority of our patients were males (81%). As for histologic type, most patients had non-squamous lung cancer (67%) as compared to 33% who had squamous lung cancer. Overall, our study reported a 24% response rate to Docetaxel including stable disease and partial response and a median progression free survival (PFS) of 3 months. The mean time interval elapsed from diagnosis to the initiation of Docetaxel was 11.5 months.
CONCLUSION: New therapeutic options should be validated for the treatment of NSCLC in the second and subsequent lines of therapy considering the poor prognosis of this disease. The chemotherapy in second and third line may keep an important role in the treatment after progression on newer agents, but it needs more evidence in prospective studies including a larger number of patients.

Keywords:  chemotherapy; immunotherapy; non-small cell lung cancer

DOI:  https://doi.org/10.18632/oncotarget.28444
Pharmaceuticals (Basel). 2023 Feb 07. pii: 255. [Epub ahead of print]16(2):

Prognostic Value of CXCL12 in Non-Small Cell Lung Cancer Patients Undergoing Tumor Resection.

Yurie Kogue, Hiroyasu Kobayashi, Yutaka Nakamura, Takatsugu Takano, Chihiro Furuta, Osamu Kawano, Taro Yasuma, Tadashi Nishimura, Corina N D'Alessandro-Gabazza, Hajime Fujimoto, Esteban C Gabazza, Tetsu Kobayashi, Ichiro Fukai.

  Adjuvant chemotherapy is commonly indicated in lung cancer patients undergoing surgical therapy because tumor recurrence is frequent. A biomarker that can predict tumor recurrence in the postoperative period is currently unavailable. CXCR4 receptor and its ligand CXCL12 play important roles in metastasis. This study investigated the value of tumor CXCL12 expression to predict prognosis and indicate adjuvant chemotherapy in non-small cell lung cancer patients. This study enrolled 82 non-small cell lung cancer patients. The expression of CXCL12 was evaluated by immunohistochemistry. The degree of CXCL12 expression was assessed using the Allred score system. Among all subjects, the progression-free survival and overall survival were significantly prolonged in cancer patients with low tumor expression of CXCL12 compared to patients with high tumor expression. Multivariate analysis showed that the increased level of CXCL12 is a significant predictor of progression-free survival and overall survival in NSCLC patients. Among subjects with high tumor CXCL12 expression, progression-free survival and overall survival were significantly improved in patients treated with adjuvant chemotherapy compared to untreated patients. These results suggest the potential value of tumor CXCL12 expression as a marker to predict prognosis and to indicate adjuvant chemotherapy after surgical tumor resection in non-small cell lung cancer patients.

Keywords:  CXCL12; CXCR4; adjuvant chemotherapy; non-small cell lung cancer; prognosis; surgical treatment

DOI:  https://doi.org/10.3390/ph16020255
BMB Rep. 2023 May 24. pii: 5912. [Epub ahead of print]

The impact of cancer cachexia on gut microbiota composition and short-chain fatty acid metabolism in a murine model.

Seung Min Jeong, Eun-Ju Jin, Shibo Wei, Ju-Hyeon Bae, Yosep Ji, Yunju Jo, Jee-Heon Jeong, Se Jin Im, Dongryeol Ryu.

This study investigates the relationship between cancer cachexia and the gut microbiota, focusing on the influence of cancer on microbial composition. Lewis lung cancer cell allografts were used to induce cachexia in mice, and body and muscle weight changes were monitored. Fecal samples were collected for targeted metabolomic analysis for short chain fatty acids and microbiome analysis. The cachexia group exhibited lower alpha diversity and distinct beta diversity in gut microbiota compared to the control group. Differential abundance analysis revealed higher Bifidobacterium and Romboutsia, but lower Streptococcus abundance in the cachexia group. Additionally, lower proportions of acetate and butyrate were observed in the cachexia group. The study observed that a significant impact of cancer cachexia on gut microbiota and their generated metabolites, indicating the host-to-gut microbiota axis.
Nat Commun. 2023 May 20. 14(1): 2897

Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma.

Danielle S Potter, Ruochen Du, Stephan R Bohl, Kin-Hoe Chow, Keith L Ligon, Raphael Bueno, Anthony Letai.

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.

DOI: https://doi.org/10.1038/s41467-023-38552-z
Am J Pathol. 2023 May 24. pii: S0002-9440(23)00173-6. [Epub ahead of print]

Mutation of TP53 confers ferroptosis resistance in lung cancer through the FOXM1/MEF2C axis.

Muyun Peng, Qikang Hu, Zeyu Wu, Bin Wang, Cheng Wang, Fenglai Yu.

  Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Our previous study found that mutations in TP53 may be associated with the "malignant" or "indolent" progression of ground glass nodules (GGO) in early lung cancer, so we wondered whether ferroptosis may also be involved in determining this biological process. Here, using in vivo and in vitro gain- and loss-of-function approaches, clinical tissue for mutation analysis and pathological research, we identified wild-type TP53 inhibits the expression of FOXM1 by binding to PGC1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis, whereas this function is absent in mutant cells, resulting in overexpression of FOXM1 and feeeptosis resistance. Mechanistically, FOXM1 can activate the transcription level of MEF2C in MAPK signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can help to deeply understand the role of TP53 in the malignant progression of lung cancer.

Keywords:  FOXM1; Ferroptosis; Lung cancer; MEF2C; Mutant TP53; PGC-1α

DOI:  https://doi.org/10.1016/j.ajpath.2023.05.003