bims-meluca 2020-04-26 papers

ESMO Open. 2020 Apr;pii: e000706. [Epub ahead of print]5(2):

STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort.

Simon Papillon-Cavanagh, Parul Doshi, Radu Dobrin, Joseph Szustakowski, Alice M Walsh.

INTRODUCTION: Somatic mutations in STK11 and KEAP1, frequently comutated in non-squamous non-small cell lung cancer (NSQ NSCLC), have been associated with poor response to immune checkpoint blockade (ICB). However, previous reports lack non-ICB controls needed to properly ascertain the predictive nature of those biomarkers. The objective of this study was to evaluate the predictive versus prognostic effect of STK11 or KEAP1 mutations in NSQ NSCLC.
METHODS: Patients diagnosed with stage IIIB, IIIC, IVA or IVB NSQ NSCLC from a real-world data cohort from the Flatiron Health Network linked with genetic testing from Foundation Medicine were retrospectively assessed. Real-world, progression-free survival (rwPFS) and overall survival (OS) were calculated from time of initiation of first-line treatment.
RESULTS: We analysed clinical and mutational data for 2276 patients including patients treated with anti-programmed death-1 (PD-1)/anti-programmed death ligand 1 (PD-L1) inhibitors at first line (n=574). Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapeutic classes and were not specifically associated with poor outcomes in ICB cohorts. There was no observable interaction between STK11 mutations and anti-PD-1/anti-PD-L1 treatment on rwPFS (HR, 1.05; 95% CI 0.76 to 1.44; p=0.785) or OS (HR, 1.13; 95% CI 0.76 to 1.67; p=0.540). Similarly, there was no observable interaction between KEAP1 mutations and treatment on rwPFS (HR, 0.93; 95% CI 0.67 to 1.28; p=0.653) or OS (HR, 0.98; 95% CI 0.66 to 1.45; p=0.913).
CONCLUSION: Our results show that STK11-KEAP1 mutations are prognostic, not predictive, biomarkers for anti-PD-1/anti-PD-L1 therapy.

Keywords: KEAP1; STK11; immune checkpoint inhibitor; non-squamous non-small cell lung cancer; prognostic

DOI: https://doi.org/10.1136/esmoopen-2020-000706

Oncol Rep. 2020 Apr 09.

HDGF enhances VEGF‑dependent angiogenesis and FGF‑2 is a VEGF‑independent angiogenic factor in non‑small cell lung cancer.

Ryoji Eguchi, Ichiro Wakabayashi.

Non‑small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer‑related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor‑A (VEGF‑A) which plays a pivotal role in tumour angiogenesis. Anti‑angiogenic therapies including VEGF‑A neutralisation have significantly improved the response rates, progression‑free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF‑independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC‑1 using serum‑free culture, to which only EBC‑1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC‑1 cells. Among the identified proteins, interleukin‑8 (IL‑8), macrophage migration inhibitory factor (MIF), galectin‑1, midkine (MK), IL‑18, galectin‑3, VEGF‑A, hepatoma‑derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF‑A and HDGF function as angiogenic factors in EBC‑1 cells. To confirm whether VEGF‑A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three‑dimensionally. Tube formation, neutralisation and RNA interference assays using the three‑dimensional (3D) culture supernatant showed that VEGF‑A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC‑1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain‑derived neurotrophic factor (BDNF), fibroblast growth factor‑2 (FGF‑2) and FGF‑5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF‑2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF‑dependent angiogenesis and that FGF‑2 is a VEGF‑independent angiogenic factor in human NSCLC cells.

DOI: https://doi.org/10.3892/or.2020.7580

Theranostics. 2020 ;10(11): 4762-4778

Hypoxia-induced lncRNA-AC020978 promotes proliferation and glycolytic metabolism of non-small cell lung cancer by regulating PKM2/HIF-1α axis.

Qian Hua, Baoming Mi, Fei Xu, Jun Wen, Li Zhao, Jianjun Liu, Gang Huang.

Rationale: Non-small cell lung cancer (NSCLC) is a deadly disease with a hallmark of aberrant metabolism. The mechanism of glycolysis associated lncRNA underlying the aggressive behaviors of NSCLC is poorly understood. Methods: The expression level of AC020978 in NSCLC was measured by quantitative real-time PCR and fluorescence in situ hybridization (FISH) assay. The biological role of AC020978 in cell proliferation and aerobic glycolysis was determined by functional experiments in vitro and in vivo. The transcription of AC020978 was assessed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assay. RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP) assays were used to identify the interaction protein with AC020978. Western blotting, in situ proximity ligation assay (PLA), and co-immunoprecipitation (co-IP) were performed to reveal the potential mechanism of AC020978. Results: The present study indicated that AC020978 was upregulated in NSCLC, significantly correlated with advanced TNM stage and poor clinical outcomes, representing as an independent prognostic predictor. Functional assays revealed AC020978's role in promoting cell growth and metabolic reprogramming. Moreover, AC020978 was an upregulated lncRNA under glucose starvation as well as hypoxia conditions, and directly transactivated by HIF-1α. Mechanistic investigations identified that AC020978 directly interacted with Pyruvate kinase isozymes M2 (PKM2) and enhanced PKM2 protein stability. Besides, this study uncovered that AC020978 could promote the nuclear translocation of PKM2 and regulate PKM2-enhanced HIF-1α transcription activity. Conclusions: Together, these data provided evidence that AC020978 conferred an aggressive phenotype to NSCLC and was a poor prognosticator. Targeting AC020978 might be an effective therapeutic strategy for NSCLC.

Keywords: AC020978; HIF-1α; Long noncoding RNAs; PKM2; aerobic glycolysis

DOI: https://doi.org/10.7150/thno.43839

Aging (Albany NY). 2020 Apr 23. 12

Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas.

Mohamed Elshaer, Ahmed Islam ElManawy, Ahmed Hammad, Akhileshwar Namani, Xiu Jun Wang, Xiuwen Tang.

KEAP1 regulates the cytoprotection induced by NRF2 and has been reported to be a candidate tumor suppressor. Recent evidence has shown that mutations in several driver genes cause aberrant DNA methylation patterns, a hallmark of cancer. However, the correlation between KEAP1 mutations and DNA methylation in lung cancer has still not been investigated. In this study, we systematically carried out an integrated multi-omics analysis to explore the correlation between KEAP1 mutations and DNA methylation and its effect on gene expression in lung adenocarcinoma (LUAD). We found that most of the DNA aberrations associated with KEAP1 mutations in LAUD were hypomethylation. Surprisingly, we found several NRF2-regulated genes among the genes that showed differential DNA methylation. Moreover, we identified 8-gene signature with altered DNA methylation pattern and elevated gene expression levels in LUAD patients with mutated KEAP1, and evaluated the prognostic value of this signature in various clinical datasets. These results establish that KEAP1 mutations are associated with DNA methylation changes capable of shaping regulatory network functions. Combining both epigenomic and transcriptomic changes along with KEAP1 mutations may provide a better understanding of the molecular mechanisms associated with the progression of lung cancer and may help to provide better therapeutic approaches.

Keywords: DNA methylation; KEAP1; NRF2; TCGA; lung cancer

DOI: https://doi.org/10.18632/aging.103068

Gen Thorac Cardiovasc Surg. 2020 Apr 23.

Postoperative prognostic nutritional index as a prognostic factor after non-small cell lung cancer surgery.

Kazuki Hayasaka, Satoshi Shiono, Katsuyuki Suzuki, Makoto Endoh, Yoshinori Okada.

OBJECTIVE: The prognostic nutritional index (PNI) is an immunonutrition index. Although preoperative PNI (pre-PNI) has been reported as a prognostic factor for patients with surgically resected non-small cell lung cancer (NSCLC), it is unclear whether postoperative PNI (post-PNI) and perioperative PNI change is a prognostic factor.
METHODS: Clinicopathological data from 262 consecutive patients who underwent lobectomy for NSCLC were collected. Pre-PNI and post-PNI were calculated within 1 month before surgery and at 1 month after surgery, respectively. We investigated which clinicopathological factors contributed to the post-PNI, the differences in prognosis according to the post-PNI status, and the impact of perioperative PNI change on prognosis.
RESULTS: We set 50 and 45 as an optimal cutoff value of pre-PNI and post-PNI for OS using a receiver operating characteristic curve. Patients who were older and male and who had lower pre-PNI, larger thoracotomy size, longer operative duration, larger blood loss during surgery, and postoperative pulmonary complications showed significantly lower post-PNI. The 5-year overall survival (OS), lung cancer-specific survival, and recurrence-free survival rates for the high/low post-PNI groups were 87.4%/58.4% (P < 0.001), 92.0%/74.8% (P = 0.001), and 80.5%/55.3% (P < 0.001). respectively. Multivariate analysis showed that the post-PNI was a significant prognostic factor (P < 0.001). We further revealed the equivalent OS with "low pre-PNI and high post-PNI" patients or "high pre-PNI and high post-PNI" patients.
CONCLUSIONS: Post-PNI status was a significant prognostic factor and perioperative PNI changes could play a significant role in the survival of patients with NSCLC after surgery.

Keywords: Non-small cell lung cancer; Overall survival; Prognostic nutritional index; Recurrence-free survival; Surgery

DOI: https://doi.org/10.1007/s11748-020-01366-7