bims-meluca 2020-11-22 papers

Pharmaceuticals (Basel). 2020 Nov 13. pii: E385. [Epub ahead of print]13(11):

Beyond LKB1 Mutations in Non-Small Cell Lung Cancer: Defining LKB1less Phenotype to Optimize Patient Selection and Treatment.

Cristina Borzi, Giulia Galli, Monica Ganzinelli, Diego Signorelli, Claudio Vernieri, Marina Chiara Garassino, Gabriella Sozzi, Massimo Moro.

LKB1 is frequently mutated in non-small cell lung cancer (NSCLC). LKB1-mutated NSCLCs often have a dismal prognosis and receive lower benefit from the currently available therapies. LKB1 acts as a cell emergency brake in low-energy conditions, by modulating the activity of crucial anabolic enzymes. Thus, loss of LKB1 activity leads to the enhancement of tumor cell proliferation also under conditions of energy shortage. This unrestrained growth may be exploited as an Achilles heel in NSCLC, i.e., by inhibiting mitochondrial respiration. Recently, clinical trials have started to investigate the efficacy of metabolism-based treatments in NSCLCs. To date, enrollment of patients within these trials is based on LKB1 loss of function status, defined by mutation in the gene or by complete absence of immunohistochemical staining. However, LKB1 impairment could be the consequence of epigenetic regulations that partially or completely abrogate protein expression. These epigenetic regulations result in LKB1 wild-type tumors with aggressiveness and vulnerabilities similar to those of LKB1-mutated ones. In this review, we introduced the definition of the "LKB1less phenotype", and we summarized all currently known features linked to this status, in order to optimize selection and treatment of NSCLC patients with impaired LKB1 function.

Keywords: LKB1; LKB1less phenotype; NSCLC; epigenetic regulation; metformin

DOI: https://doi.org/10.3390/ph13110385

Onco Targets Ther. 2020 ;13 11459-11470

Long Noncoding RNA LINC00551 Suppresses Glycolysis and Tumor Progression by Regulating c-Myc-Mediated PKM2 Expression in Lung Adenocarcinoma.

Li Wang, Huishan Wang, Bining Wu, Chun Zhang, Hualin Yu, Xueyan Li, Qinjue Wang, Xiaoli Shi, Chengfeng Fan, Dayu Wang, Jing Luo, Jinsong Yang.

Background: Lung adenocarcinoma (LUAD) is a leading cause of mortality associated with cancer globally. Thus, it is essential to elucidate its tumorigenesis and prognosis. Accumulating evidence shows that long noncoding RNAs (lncRNAs) play important roles in the occurrence and progression of tumors by regulating their glucose metabolism.
Methods: Bioinformatics analysis was performed to explore the expression of LINC00551 in LUAD. The level of LINC00551 in LUAD cells and tissues was detected by RT-qPCR. CCK-8, colony formation, EDU and transwell assays were conducted to evaluate the cell growth and migration of LUAD cells (A549 and PC9). High throughput sequencing was used to discover the downstream genes of LINC00551. The metabolic function of LUAD cells was identified by glucose uptake and lactate production assays. Furthermore, tumor xenografts were established to investigate the effects of LINC00551 on tumor growth in vivo.
Results: Herein, we found that LINC00551 was low-expressed in LUAD, and its level correlated with clinical prognosis. Ectopic expression of LINC00551 inhibited the proliferation and migration of LUAD cells (A549 and PC9). High throughput sequencing and gene enrichment analysis revealed that LINC0551 may be involved in metabolic pathway. Glucose uptake and lactate production assays suggested that LINC00551 suppressed glycolysis of LUAD cells. Mechanistically, our work revealed that LINC00551 inhibited glycolysis in LUAD cells by impairing c-Myc-mediated transcription of an important glycolysis-related enzyme PKM2.
Conclusion: In summary, our study identifies LINC00551 as a tumor suppressor in LUAD and implicates the LINC00551/c-Myc/PKM2 axis in the glycolytic remodeling of LUAD.

Keywords: LINC00551; PKM2; c-Myc; glycolysis; lung adenocarcinoma

DOI: https://doi.org/10.2147/OTT.S273797

Oncogenesis. 2020 Nov 19. 9(11): 102

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Silke Nothdurft, Clotilde Thumser-Henner, Frank Breitenbücher, Ross A Okimoto, Madeleine Dorsch, Christiane A Opitz, Ahmed Sadik, Charlotte Esser, Michael Hölzel, Saurabh Asthana, Jan Forster, Daniela Beisser, Sophie Kalmbach, Barbara M Grüner, Trever G Bivona, Alexander Schramm, Martin Schuler.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.

DOI: https://doi.org/10.1038/s41389-020-00286-8

J Immunother Cancer. 2020 Nov;pii: e001674. [Epub ahead of print]8(2):

Baseline prognostic nutritional index and changes in pretreatment body mass index associate with immunotherapy response in patients with advanced cancer.

Paul Johannet, Amelia Sawyers, Yingzhi Qian, Samuel Kozloff, Nicholas Gulati, Douglas Donnelly, Judy Zhong, Iman Osman.

BACKGROUND: Recent research suggests that baseline body mass index (BMI) is associated with response to immunotherapy. In this study, we test the hypothesis that worsening nutritional status prior to the start of immunotherapy, rather than baseline BMI, negatively impacts immunotherapy response.
METHODS: We studied 629 patients with advanced cancer who received immune checkpoint blockade at New York University. Patients had melanoma (n=268), lung cancer (n=128) or other primary malignancies (n=233). We tested the association between BMI changes prior to the start of treatment, baseline prognostic nutritional index (PNI), baseline BMI category and multiple clinical end points including best overall response (BOR), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).
RESULTS: Decreasing pretreatment BMI and low PNI were associated with worse BOR (p=0.04 and p=0.0004), ORR (p=0.01 and p=0.0005), DCR (p=0.01 and p<0.0001), PFS (p=0.02 and p=0.01) and OS (p<0.001 and p<0.001). Baseline BMI category was not significantly associated with any treatment outcomes.
CONCLUSION: Standard of care measures of worsening nutritional status more accurately associate with immunotherapy outcomes than static measurements of BMI. Future studies should focus on determining whether optimizing pretreatment nutritional status, a modifiable variable, leads to improvement in immunotherapy response.

Keywords: immunotherapy

DOI: https://doi.org/10.1136/jitc-2020-001674

Interact Cardiovasc Thorac Surg. 2020 Nov 19. pii: ivaa213. [Epub ahead of print]

Does metformin improve the efficacy of standard epidermal growth factor receptor-tyrosine kinase inhibitor treatment for patients with advanced non-small-cell lung cancer?

Zhangyu Lin, Guangchen Li, Xinyu Xu, Jiandong Mei.

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether metformin improved the efficacy of standard epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer. A total of 99 papers were found using the reported search, of which 4 represented the best evidence to answer this clinical question. The authors, journal, publication date, country, study type, treatment regimen, relevant outcomes and results of these papers are tabulated. We concluded that the addition of metformin to EGFR-TKI might improve the survival of patients with EGFR-mutated non-small-cell lung cancer and diabetes mellitus type 2. However, for non-diabetic non-small-cell lung cancer patients with EGFR mutation, the efficiency of additional metformin in EGFR-TKI treatment remains unclear because of the conflicting results of only 2 available studies.

Keywords: Epidermal growth factor receptor-tyrosine kinase inhibitor; Metformin; Non-small-cell lung cancer; Review

DOI: https://doi.org/10.1093/icvts/ivaa213