bims-meluca 2023-03-19 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–03–19
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer.
Prognostic factors and the prognostic role of inflammation indices in malignant pleural mesothelioma.
MAX transcriptionally enhances PD-L1 to inhibit CD8+ T cell-mediated killing of lung adenocarcinoma cells.
IL-36 expression is increased in NSCLC with IL-36 stimulation of lung cancer cells promoting a pro-tumorigenic phenotype.
Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis.
Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells.
UHMK1 promotes lung adenocarcinoma oncogenesis by regulating the PI3K/AKT/mTOR signaling pathway.

Sci Adv. 2023 Mar 15. 9(11): eadd3243

HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer.

Lillian J Eichner, Stephanie D Curtis, Sonja N Brun, Caroline K McGuire, Irena Gushterova, Joshua T Baumgart, Elijah Trefts, Debbie S Ross, Tammy J Rymoff, Reuben J Shaw.

HDAC3 is one of the main targets of histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. We identified a critical role for HDAC3 in Kras-mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical previously unidentified target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras/LKB1-mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the Kras/LKB1 GEMM.

DOI: https://doi.org/10.1126/sciadv.add3243
Turk Gogus Kalp Damar Cerrahisi Derg. 2023 Jan;31(1): 105-115

Prognostic factors and the prognostic role of inflammation indices in malignant pleural mesothelioma.

Senar Ebinç, Zeynep Oruç, Ziya Kalkan, Oğur Karhan, Zuhat Urakçı, Mehmet Küçüköner, Muhammet Ali Kaplan, Işıkdoğan Abdurrahman.

   Background: In this study, we aimed to investigate the prognostic factors of malignant pleural mesothelioma and the prognostic value of inflammation indices in malignant pleural mesothelioma.
Methods: Between January 2002 and December 2019, a total of 132 patients (74 males, 58 females; mean age: 55 years; range, 31 to 79 years) diagnosed with malignant pleural mesothelioma were retrospectively analyzed. Patients" demographic data and laboratory results were recorded. The prognostic value of the following five inflammation indices was evaluated: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, advanced lung cancer inflammation index, C-reactive protein/albumin ratio, and prognostic nutritional index.
Results: Of all patients, 81% (n=107) were aged 65 or older and 61.4% (n=81) had an epithelioid histology. Of 12 variables examined in the multivariate analysis for their relationship with survival, age ≥65 years, non-epithelioid subtype, and prognostic nutritional index <40 were found to be poor prognostic factors. Based on the score constructed from these factors, the good prognostic group (score 0-1) had a median overall survival of 21 months and a one-year survival rate of 77.9%, while the poor prognostic group (score 2-3) had a median overall survival of nine months and a one-year survival rate of 29.7%.
Conclusion: Our study results indicate that age ≥65 years, prognostic nutritional index <40, and non-epithelioid histological subtype are poor prognostic factors of malignant pleural mesothelioma.

Keywords:  Inflammation indices; malignant pleural mesothelioma; prognostic nutritional index; prognostic score

DOI:  https://doi.org/10.5606/tgkdc.dergisi.2023.23365
Cell Immunol. 2023 Mar 09. pii: S0008-8749(23)00045-X. [Epub ahead of print]386 104706

MAX transcriptionally enhances PD-L1 to inhibit CD8+ T cell-mediated killing of lung adenocarcinoma cells.

Dongwei Huang, Xueni Wang, Yunfeng Qian, Jun Wu, Binzhuan Chen, Deming Zhang, Fengying Dong, Yongqiang Li.

  Immune checkpoint blockade (ICB) therapies, such as monoclonal antibodies against the PD-1/PD-L1 immune checkpoint pathway, have been a major breakthrough in the treatment of lung cancer especially lung adenocarcinoma (LUAD), but their effectiveness is limited. High expression of PD-L1 in tumor cells is one of the key reasons evading immune surveillance, yet the mechanisms that regulate PD-L1 expression are not fully understood. By analyzing the chromatin immunoprecipitation sequencing data of MYC-associated X-factor (MAX) based on lung cancer cell lines, we found that the transcriptional regulator MAX is able to bind to the promoter region of the PD-L1 gene. Further, we performed several molecular biology experiments to determine that MAX promotes PD-L1 transcription in LUAD cells, which in turn assists LUAD cells to evade killing by CD8+ T cells, an effect that can be reversed by anti-PD-L1 antibody. In LUAD, the expression of MAX is positively correlated with PD-L1 and the infiltration of CD8+ T cells. Importantly, we further identified that high expression of the MAX/PD-L1 axis is associated with poor overall survival and fist progression of patients with LUAD. Thus, this study sheds light on the mechanism by which MAX inhibits CD8+ T cell-mediated killing of LUAD cells by activating PD-L1 transcription, and MAX may serve as a potential combinatorial target for ICB therapies that block the PD-1/PD-L1 pathway in LUAD.

Keywords:  Lung adenocarcinoma; Lung cancer; MAX; PD-L1; Transcriptional regulation

DOI:  https://doi.org/10.1016/j.cellimm.2023.104706
Cytokine. 2023 Mar 15. pii: S1043-4666(23)00048-0. [Epub ahead of print]165 156170

IL-36 expression is increased in NSCLC with IL-36 stimulation of lung cancer cells promoting a pro-tumorigenic phenotype.

Kevin James Baker, Emily Buskiewicz, Méabh Finucane, Adeleine Chelliah, Louise Burke, Aileen Houston, Elizabeth Brint.

  The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, and have been shown to play a role in the pathogenesis of respiratory diseases such as asthma and COPD. Given the common aetiological links between COPD and lung cancer development, as well as the involvement of other IL-1 family members in lung tumorigenesis, the aim of this work was to investigate the role of IL-36 cytokines in the pathogenesis of lung cancer. In this study we demonstrate that expression of IL-36 cytokines and receptor mRNA and protein are significantly increased in lung cancer tissue compared to adjacent non-tumour tissue. In vitro assays showed that stimulation of two lung cancer cell lines, SKMES-1 human squamous cell and LLC murine lung cancer, with IL-36R agonists resulted in increased cellular migration and proliferation. All IL-36 cytokines induced the expression of pro-inflammatory chemokines in both lung cancer cell lines with synergistic effects identified upon co-stimulation of cells with IL-17, IL-22 and TNFα. Furthermore, we report that IL-36 cytokines induce protein expression of the immune checkpoint inhibitor protein PD-L1 on lung cancer cells. Taken together, this data indicates that targeting IL-36R signalling may be a useful targeted therapy for lung cancer patients with IL-36R+ cancer cells.

Keywords:  IL-1 family; IL-36; Lung cancer; Tumorigenesis

DOI:  https://doi.org/10.1016/j.cyto.2023.156170
Open Med (Wars). 2023 ;18(1): 20230653

Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis.

Xiaodong Gu, Jinfei Si, Yelan Guan, Yibing Xu, Lan Shao, Yiping Zhang, Chunwei Xu, Weiwei Pan, Yuanzhi Lu, Zhengbo Song, Wenxian Wang.

  The efficacy of immune checkpoint inhibitors (ICIs) on KRAS-mutant advanced non-small cell lung cancer (NSCLC) remains controversial. This retrospective study compared the effects of ICIs treatment and chemotherapy on the prognosis of patients with KRAS-mutant advanced NSCLC and different mutant subtypes in the real world. The study included 95 patients with KRAS-mutant advanced NSCLC. Patients treated with first-line ICIs plus platinum-containing chemotherapy had better progression-free survival (PFS) (7.4 vs 4.5 months, P = 0.035) and overall survival (OS) (24.1 vs 13.2 months, P = 0.007) than those receiving platinum-containing chemotherapy alone, and second-line ICI monotherapy was associated with better PFS (4.8 vs 3.0 months, P = 0.043) and OS (18.0 vs 13.8 months, P = 0.013) than chemotherapy monotherapy. There was no significant difference in PFS (5.267 vs 6.734 months, P = 0.969) and OS (19.933 vs 20.933 months, P = 0.808) between patients with KRAS-mutant and KRAS-wild-type NSCLC treated with ICIs or between KRAS G12C and KRAS non-G12C patients (PFS: 8.1 vs 4.8 months, P = 0.307; OS: 21.3 vs 21.8 months, P = 0.434). In summary, patients with advanced NSCLC with KRAS mutations can benefit from ICIs, but no difference between KRAS mutant subtypes was observed.

Keywords:  ICIs; KRAS; KRAS G12C; NSCLC; chemotherapy

DOI:  https://doi.org/10.1515/med-2023-0653
Cell Commun Signal. 2023 Mar 13. 21(1): 58

Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells.

Anudari Letian, Eyoel Yemanaberhan Lemma, Paola Cavaliere, Noah Dephoure, Nasser K Altorki, Timothy E McGraw.

BACKGROUND: PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.g., mutant EGF receptor tumors) are generally poor responders. Although PD-L1 is best characterized as a transmembrane PD1 ligand, the emerging view is that PD-L1 has functions independent of activating PD1 signaling. It is not known whether these cell-intrinsic functions of PD-L1 are shared among non-transformed and transformed cells, if they vary among cancer molecular subtypes, or if they are impacted by anti-PD-L1 therapy.
METHODS: Here we use quantitative microscopy techniques and APEX2 proximity mapping to describe the behavior of PD-L1 and to identify PD-L1's proximal proteome in human lung epithelial cells.
RESULTS: Our data reveal growth factor control of PD-L1 recycling as a mechanism for acute and reversible regulation of PD-L1 density on the plasma membrane. In addition, we describe novel PD-L1 biology restricted to mutant EGFR cells. Anti-PD-L1 antibody treatment of mutant EGFR cells perturbs cell intrinsic PD-L1 functions, leading to reduced cell migration, increased half-life of EGFR and increased extracellular vesicle biogenesis, whereas anti-PD-L1 antibody does not induce these changes in wild type EGFR cells.
CONCLUSIONS: Growth factor acute regulation of PD-L1 trafficking, by contributing to the control of plasma membrane density, might contribute to the regulation of PD-L1's immune checkpoint activity, whereas the specific effects of anti-PD-L1 on mutant EGFR cells might contribute to the poor anti-PD-L1 response of mutant EGFR tumors. Video Abstract.

DOI: https://doi.org/10.1186/s12964-023-01084-6
Thorac Cancer. 2023 Mar 15.

UHMK1 promotes lung adenocarcinoma oncogenesis by regulating the PI3K/AKT/mTOR signaling pathway.

Yongmeng Li, Shuai Wang, Kai Jin, Wenxing Jin, Libo Si, Huiying Zhang, Hui Tian.

   BACKGROUND: Effective targeted therapy for lung adenocarcinoma (LUAD), the number one cancer killer worldwide, continues to be a difficult problem because of the limitation of number of applicable patients and acquired resistance. Identifying more promising drug targets for LUAD treatment holds immense clinical significance. Recent studies have revealed that the U2 auxiliary factor (U2AF) homology motif kinase 1 (UHMK1) is a robust pro-oncogenic factor in many cancers. However, its biological functions and the underlying molecular mechanisms in LUAD have not been investigated.
METHODS: The UHMK1 expression in LUAD cells and tissues was evaluated by bioinformatics analysis, immunohistochemistry (IHC), western blotting (WB), and real time quantitative polymerase chain reaction (RT-qPCR) assays. A series of gain- and loss-of-function experiments for UHMK1 were carried out to investigate its biological functions in LUAD in vitro and in vivo. The mechanisms underlying UHMK1's effects in LUAD were analyzed by transcriptome sequencing and WB assays.
RESULTS: UHMK1 expression was aberrantly elevated in LUAD tumors and cell lines and positively correlated with tumor size and unfavorable patient prognosis. Functionally, UHMK1 displayed robust pro-oncogenic capacity in LUAD and mechanistically exerted its biological effects via the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway.
CONCLUSION: UHMK1 is a potent oncogene in LUAD. Targeting UHMK1 may significantly improve the effect of LUAD treatment via inhibiting multiple biological ways of LUAD progression.

Keywords:  PI3K/AKT/mTOR signaling pathway; U2AF homology motif kinase 1 (UHMK1); lung adenocarcinoma (LUAD); metastasis; proliferation

DOI:  https://doi.org/10.1111/1759-7714.14850