bims-meluca 2024-01-14 papers

Lung Cancer. 2023 Dec 27. pii: S0169-5002(23)00987-X. [Epub ahead of print]188 107449

SFXN1 as a potential diagnostic and prognostic biomarker of LUAD is associated with 18F-FDG metabolic parameters.

Yao-Hua Zhang, Xu-Sheng Liu, Yan Gao, Ling-Ling Yuan, Zhong-Min Huang, Yu Zhang, Zi-Yue Liu, Yi Yang, Xiao-Yu Liu, Chang-Bin Ke, Zhi-Jun Pei.

BACKGROUND: Sideroflexin 1 (SFXN1) has been discovered as a novel tumor marker for lung adenocarcinoma, but data on its importance in the development of lung adenocarcinoma is still limited. This study evaluated the correlation between SFXN1 and parameters related to 18F-flurodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), and further explored the role of SFXN1 in the value-added and glycolytic processes of LUAD.
METHOD: The expression and prognostic value of SFXN1 mRNA in LUAD were analyzed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data base. Retrospective analysis of 18F-FDG PET imaging and metabolic parameters in 42 patients to explore the relationship between the expression of SFXN1 and glucose metabolism levels in lung adenocarcinoma and its clinical significance. H1975 cells were selected as the in vitro research object, and the biological effects of SFXN1 on LUAD were further elucidated through Edu proliferation assay, CCK8 activity assay, wound healing experiment, and cell flow cytometry.
RESULT: SFXN1 is highly expressed in various tumors, including LUAD, and its high expression can serve as an independent predictor of overall survival in lung adenocarcinoma. In addition, the expression of SFXN1 in LUAD was significantly correlated with 18F-FDG PET/CT parameters: maximum and average standardized uptake values (SUVmax and SUVmean), as well as total lesion glycolysis (TLG) (rho = 0.574, 0.589, and 0.338, p < 0.05), which can predict the expression of SFXN1 with an accuracy of 0.934. In vitro functional experiments have shown that knocking down SFXN1 inhibits the proliferation and migration of LUAD cells, promotes cell apoptosis, and may inhibit tumor activity by regulating the expression of glycolytic related genes SLC2A1, HK2, GPI, ALDOA, GAPDH, ENO1, PKM, and LDHA.
CONCLUSION: The overexpression of SFXN1 is closely related to FDG uptake, and SFXN1, as a promising prognostic biomarker, may mediate the development of LUAD through the glycolytic pathway.

Keywords: (18)F-FDG PET; Glycolysis; Lung adenocarcinoma; Prognostic biomarker; Proliferation; SFXN1

DOI: https://doi.org/10.1016/j.lungcan.2023.107449

Cancers (Basel). 2024 Jan 04. pii: 230. [Epub ahead of print]16(1):

Cachexia and Sarcopenia in Oligometastatic Non-Small Cell Lung Cancer: Making a Potential Curable Disease Incurable?

Valentina Bartolomeo, Mandy Jongbloed, Wouter R P H van de Worp, Ramon Langen, Juliette Degens, Lizza E L Hendriks, Dirk K M de Ruysscher.

Among patients with advanced NSCLC, there is a group of patients with synchronous oligometastatic disease (sOMD), defined as a limited number of metastases detected at the time of diagnosis. As cachexia and sarcopenia are linked to poor survival, incorporating this information could assist clinicians in determining whether a radical treatment should be administered. In a retrospective multicenter study, including all patients with adequately staged (FDG-PET, brain imaging) sOMD according to the EORTC definition, we aimed to assess the relationship between cachexia and/or sarcopenia and survival. Of the 439 patients that were identified between 2015 and 2021, 234 met the criteria for inclusion and were included. The median age of the cohort was 67, 52.6% were male, and the median number of metastasis was 1. Forty-six (19.7%) patients had cachexia, thirty-four (14.5%) had sarcopenia and twenty-one (9.0%) had both. With a median follow-up of 49.7 months, median PFS and OS were 8.6 and 17.3 months, respectively. Moreover, a trend toward longer PFS was found in patients without cachexia and sarcopenia compared to those with cachexia and/or sarcopenia. In multivariate analysis, cachexia and sarcopenia were not associated with an inferior survival, irrespective of receiving radical treatment. High CRP was associated with inferior survival and could be a prognostic factor, helping the decision of clinicians in selecting patients who may benefit from the addition of LRT. However, despite the homogeneous definition of oligometastatic disease and the adequate staging, our subgroups were small. Therefore, further studies are needed to better understand our hypothesis and generating findings.

Keywords: NSCLC; cachexia; intention to treat; overall survival; progression-free survival; psoas muscle index; sarcopenia; synchronous oligometastatic disease; toxicity

DOI: https://doi.org/10.3390/cancers16010230

Redox Biol. 2024 Jan 04. pii: S2213-2317(24)00007-7. [Epub ahead of print]69 103031

Oncogenic KEAP1 mutations activate TRAF2-NFκB signaling to prevent apoptosis in lung cancer cells.

Ashik Jawahar Deen, Simone Adinolfi, Jouni Härkönen, Tommi Patinen, Xiaonan Liu, Tuomo Laitinen, Piia Takabe, Kirsi Kainulainen, Sanna Pasonen-Seppänen, Lisa M Gawriyski, Uma Thanigai Arasu, Ilakya Selvarajan, Petri Mäkinen, Hanna Laitinen, Emilia Kansanen, Minna U Kaikkonen, Antti Poso, Markku Varjosalo, Anna-Liisa Levonen.

The Kelch-like ECH-associated protein 1 (KEAP1) - Nuclear factor erythroid 2 -related factor 2 (NRF2) pathway is the major transcriptional stress response system in cells against oxidative and electrophilic stress. NRF2 is frequently constitutively active in many cancers, rendering the cells resistant to chemo- and radiotherapy. Loss-of-function (LOF) mutations in the repressor protein KEAP1 are common in non-small cell lung cancer, particularly adenocarcinoma. While the mutations can occur throughout the gene, they are enriched in certain areas, indicating that these may have unique functional importance. In this study, we show that in the GSEA analysis of TCGA lung adenocarcinoma RNA-seq data, the KEAP1 mutations in R320 and R470 were associated with enhanced Tumor Necrosis Factor alpha (TNFα) - Nuclear Factor kappa subunit B (NFκB) signaling as well as MYC and MTORC1 pathways. To address the functional role of these hotspot mutations, affinity purification and mass spectrometry (AP-MS) analysis of wild type (wt) KEAP1 and its mutation forms, R320Q and R470C were employed to interrogate differences in the protein interactome. We identified TNF receptor associated factor 2 (TRAF2) as a putative protein interaction partner. Both mutant KEAP1 forms showed increased interaction with TRAF2 and other anti-apoptotic proteins, suggesting that apoptosis signalling could be affected by the protein interactions. A549 lung adenocarcinoma cells overexpressing mutant KEAP1 showed high TRAF2-mediated NFκB activity and increased protection against apoptosis, XIAP being one of the key proteins involved in anti-apoptotic signalling. To conclude, KEAP1 R320Q and R470C and its interaction with TRAF2 leads to activation of NFκB pathway, thereby protecting against apoptosis.

Keywords: Apoptosis; KEAP1; Lung cancer; NFκB; TNFα; TRAF2

DOI: https://doi.org/10.1016/j.redox.2024.103031

Clin Transl Oncol. 2024 Jan 06.

Identification of non-actionable mutations with prognostic and predictive value in patients with advanced or metastatic non-small cell lung cancer.

Mariano Provencio-Pulla, Diego Pérez-Parente, Sara Olson, Haroon Hasan, Begoña Campos Balea, Delvys Rodríguez-Abreu, Marta López-Brea Piqueras, Navdeep Pal, Samantha Wilkinson, Esther Vilas, Pedro Ruiz-Gracia, Manuel Cobo-Dols.

INTRODUCTION: Lung cancer is one of the most prevalent cancers and the leading cause of cancer death. Advanced non-small cell lung cancer (aNSCLC) patients frequently harbor mutations that impact their survival outcomes. There are limited data regarding the prognostic and predictive significance of these mutations on survival outcomes in the real-world setting.
METHODS: This observational retrospective study analyzed de-identified electronic medical records from the Flatiron Health Clinico-Genomic and FoundationCore® databases to identify patients with aNSCLC who initiated first-line immune checkpoint inhibitors (ICI; alone or in combination) or chemotherapy under routine care between 2016 and 2021. The primary objectives were to assess the prevalence of non-actionable mutations and to determine their association with overall survival (OS). Real-world progression-free survival (rwPFS) and real-world response (rwR) were investigated as secondary exploratory outcomes.
RESULTS: Based on an assessment of 185 non-actionable mutations in 2999 patients, the most prevalent mutations were TP53 (70%), KRAS (42%), CDKN2A/B (31%), and STK11 (21%). STK11, KEAP1, and CDKN2A/B mutations were significantly associated with lower rwR, shorter rwPFS and OS. KRAS mutations were clinically associated with shorter rwPFS in CIT-treated patients. Subgroup analysis revealed that fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations. Accordingly, long-term survivors (LTS) showed a significantly lower prevalence of these mutations.
CONCLUSION: Our results provide evidence on the prognostic value of STK11, KEAP1, and CDKN2A/B mutations in patients with aNSCLC. Further research is required to better understand the implications of these findings on patient management and future trial design and treatment selection.

Keywords: NSCLC; Non-actionable mutations; Prognosis; Real-world; Survival

DOI: https://doi.org/10.1007/s12094-023-03362-8