Targeting metabolism and AMP-activated kinase with metformin to sensitize non-small cell lung cancer (NSCLC) to cytotoxic therapy: translational biology and rationale for current clinical trials

Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept.

• Publication year

  2017

• Venue

  OncoTarget

• Publication date

  2017-04-27

• Fields of study

  Medicine

• Identifiers
  DOI 10.18632/oncotarget.17496PMID 28915708PMCID 5593680
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small cell lung cancer in preclinical models

  2016cited by this paper
• Cancer statistics, 2016

  2016cited by this paper
• Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy.

  2016influential reference
• Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment.

  2016cited by this paper
• Are Metformin Doses Used in Murine Cancer Models Clinically Relevant?

  2016cited by this paper
• Metformin Pharmacokinetics in Mouse Tumors: Implications for Human Therapy.

  2016cited by this paper
• Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase

  2016cited by this paper
• Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

  2015cited by this paper
• Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma

  2015cited by this paper
• Inhibiting GLUT-1 expression and PI3K/Akt signaling using apigenin improves the radiosensitivity of laryngeal carcinoma in vivo.

  2015cited by this paper
• Suppression of tumor angiogenesis by metformin treatment via a mechanism linked to targeting of HER2/HIF-1α/VEGF secretion axis

  2015cited by this paper
• Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline.

  2015influential reference
• Metformin enhances radiation response of ECa109 cells through activation of ATM and AMPK.

  2015cited by this paper
• Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis.

  2015influential reference
• Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway.

  2015cited by this paper
• Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice.

  2015cited by this paper
• Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis

  2015cited by this paper
• Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α

  2014cited by this paper
• Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells

  2014cited by this paper
• The effects of nonspecific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer

  2014cited by this paper
• Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

  2014cited by this paper
• Metformin: from mechanisms of action to therapies.

  2014cited by this paper
• Effect of mitochondrial metabolism-interfering agents on cancer cell mitochondrial function and radio/chemosensitivity

  2014cited by this paper
• AMP-activated protein kinase (AMPK) beyond metabolism

  2014cited by this paper
• Managing lipid metabolism in proliferating cells: new perspective for metformin usage in cancer therapy.

  2014cited by this paper
• Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma.

  2014influential reference
• Targeting SREBP-1-driven lipid metabolism to treat cancer.

  2014cited by this paper
• K‑ras gene mutation as a predictor of cancer cell responsiveness to metformin.

  2013cited by this paper
• Metformin use and improved response to therapy in esophageal adenocarcinoma

  2013cited by this paper
• Another Surprise from Metformin: Novel Mechanism of Action via K-Ras Influences Endometrial Cancer Response to Therapy

  2013cited by this paper
• Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line

  2013cited by this paper
• Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation.

  2013cited by this paper
• LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.

  2013cited by this paper
• The Warburg effect: insights from the past decade.

  2013cited by this paper
• Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin–sensitizing effects of metformin

  2013cited by this paper
• Cellular fatty acid metabolism and cancer.

  2013cited by this paper
• Surgery versus stereotactic radiotherapy for patients with early‐stage non–small cell lung cancer

  2013cited by this paper
• ATP Citrate Lyase Mediates Resistance of Colorectal Cancer Cells to SN38

  2013cited by this paper
• The Fatty Acid Synthase Inhibitor Orlistat Reduces the Growth and Metastasis of Orthotopic Tongue Oral Squamous Cell Carcinomas

  2013cited by this paper
• Synergistic Effects of Metformin Treatment in Combination with Gefitinib, a Selective EGFR Tyrosine Kinase Inhibitor, in LKB1 Wild-type NSCLC Cell Lines

  2013influential reference
• Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK

  2013influential reference
• Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

  2013cited by this paper
• Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap)

  2013influential reference
• ATP-citrate lyase: a key player in cancer metabolism.

  2012cited by this paper
• Chronic modulation of AMP-Kinase, Akt and mTOR pathways by ionizing radiation in human lung cancer xenografts

  2012cited by this paper
• Everolimus exhibits efficacy as a radiosensitizer in a model of non-small cell lung cancer.

  2012cited by this paper
• ATP-citrate lyase: a key player in cancer metabolism.

  2012cited by this paper
• Metformin does not alter the risk of lung cancer: a case-control analysis.

  2012cited by this paper
• Ionizing radiation regulates the expression of AMP-activated protein kinase (AMPK) in epithelial cancer cells: modulation of cellular signals regulating cell cycle and survival.

  2012influential reference
• Mortality After Incident Cancer in People With and Without Type 2 Diabetes

  2012cited by this paper
• Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

  2012cited by this paper
• Sestrin2 Modulates AMPK Subunit Expression and Its Response to Ionizing Radiation in Breast Cancer Cells

  2012cited by this paper
• The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

  2012cited by this paper
• The effect of metformin and thiazolidinedione use on lung cancer in diabetics

  2012cited by this paper
• The Influence of Type 2 Diabetes and Glucose-Lowering Therapies on Cancer Risk in the Taiwanese

  2012cited by this paper
• Cancer Risk in Diabetic Patients Treated with Metformin: A Systematic Review and Meta-analysis

  2012cited by this paper
• Caveolin‐1 is essential for metformin inhibitory effect on IGF1 action in non‐small‐cell lung cancer cells

  2012cited by this paper
• Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen‐activated protein Kinase (MAPK) and Phosphatidylinositol‐3‐kinase (PI3K)/AKT pathways

  2012cited by this paper
• Statins and cancer: current and future prospects.

  2012influential reference
• MortalityAfter Incident Cancer in People With andWithout Type 2 Diabetes Impact of metformin on survival

  2012cited by this paper
• Are the results of RTOG 0617 mysterious?

  2012cited by this paper
• Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials

  2012cited by this paper
• Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan.

  2012cited by this paper
• Antiproliferative action of metformin in human lung cancer cell lines

  2012cited by this paper
• Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status

  2012cited by this paper
• Antiproliferative action of metformin in human lung cancer cell lines.

  2012cited by this paper
• AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.

  2011cited by this paper
• Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324.

  2011cited by this paper
• Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types.

  2011cited by this paper
• Prognostic influence of metformin as first‐line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes

  2011cited by this paper
• Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency

  2011cited by this paper
• The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

  2011cited by this paper
• Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer

  2011cited by this paper
• Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth

  2011cited by this paper
• Clinical Pharmacokinetics of Metformin

  2011cited by this paper
• Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410.

  2011cited by this paper
• TP53 Disruptive Mutations Lead to Head and Neck Cancer Treatment Failure through Inhibition of Radiation-Induced Senescence

  2011cited by this paper
• Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

  2011cited by this paper
• Metformin activates an Ataxia Telangiectasia Mutated (ATM)/Chk2-regulated DNA damage-like response

  2011cited by this paper
• Metabolic genes in cancer: their roles in tumor progression and clinical implications.

  2010cited by this paper
• The effect of metformin and thiazolidinedione use on lung cancer in diabetics

  2010cited by this paper
• Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells

  2010cited by this paper
• Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase.

  2010cited by this paper
• Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives.

  2010cited by this paper
• ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

  2010cited by this paper
• The tumor microenvironment in non-small-cell lung cancer.

  2010cited by this paper
• β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK)

  2010cited by this paper
• Ionizing radiation activates AMP-activated kinase (AMPK): a target for radiosensitization of human cancer cells.

  2010cited by this paper
• Metformin Prevents Tobacco Carcinogen–Induced Lung Tumorigenesis

  2010cited by this paper
• Acetyl-CoA carboxylase-a as a novel target for cancer therapy.

  2010cited by this paper
• Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

  2009cited by this paper
• mTOR signaling at a glance

  2009influential reference
• AMPK in Health and Disease.

  2009cited by this paper
• Mitotic kinase dynamics of the active form of AMPK (Phospho-AMPKαThr172) in human cancer cells

  2009cited by this paper
• The active form of the metabolic sensor AMP-activated protein kinase α (AMPKα) directly binds the mitotic apparatus and travels from centrosomes to the spindle midzone during mitosis and cytokinesis

  2009cited by this paper
• p21 in cancer: intricate networks and multiple activities

  2009cited by this paper
• Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations.

  2009cited by this paper
• If mammalian target of metformin indirectly is mammalian target of rapamycin, then the insulin-like growth factor-1 receptor axis will audit the efficacy of metformin in cancer clinical trials.

  2009cited by this paper
• Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.

  2009cited by this paper
• The influence of glucose-lowering therapies on cancer risk in type 2 diabetes

  2009cited by this paper

• Metformin and Oncogenic Pathways: Crosstalk Between Energy Sensing and Tumor Progression.

  2026cites this paper
• Rewiring cancer metabolism: oncogenic signaling pathways and targeted therapeutics

  2025cites this paper
• Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected locally advanced non-small cell lung cancer treated with chemoradiotherapy

  2024cites this paper
• LKB1 Mutations Enhance Radiosensitivity in Non-Small Cell Lung Cancer Cells by Inducing G2/M Cell Cycle Phase Arrest.

  2024cites this paper
• Metformin suppresses lung adenocarcinoma by downregulating long non-coding RNA (lncRNA) AFAP1-AS1 and secreted phosphoprotein 1 (SPP1) while upregulating miR-3163

  2022cites this paper
• The PI3K/Akt/mTOR pathway in lung cancer; oncogenic alterations, therapeutic opportunities, challenges, and a glance at the application of nanoparticles

  2022cites this paper
• Advances in metformin-based metabolic therapy for non-small cell lung cancer

  2022cites this paper
• Investigation into the role of anti-diabetic agents in cachexia associated with metastatic cancer.

  2021cites this paper
• Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

  2021cites this paper
• Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1

  2021influential citation
• A systematic review and meta-analysis on the efficacy and safety of metformin as adjunctive therapy among women with metastatic breast cancer.

  2021cites this paper
• Combined metformin-salicylate treatment provides improved anti-tumor activity and enhanced radiotherapy response in prostate cancer; drug synergy at clinically relevant doses

  2021cites this paper
• Therapeutic irradiation in the management of gynecological cancer and predictability of radiation-induced complications

  2021cites this paper
• Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non-Small Cell Lung Cancer: The NRG-LU001 Phase 2 Randomized Clinical Trial.

  2021cites this paper
• Metformin in Combination With Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: The OCOG-ALMERA Randomized Clinical Trial.

  2021cites this paper
• RETRACTED ARTICLE: The Lnc LINC00461/miR-30a-5p facilitates progression and malignancy in non-small cell lung cancer via regulating ZEB2

  2020cites this paper
• Activation of Adenosine Monophosphate—Activated Protein Kinase Reduces the Onset of Diet‐Induced Hepatocellular Carcinoma in Mice

  2020cites this paper
• Exploiting Cancer’s Tactics to Make Cancer a Manageable Chronic Disease

  2020cites this paper
• Fraxetin inhibits the proliferation of RL95-2 cells through regulation of metabolism.

  2020cites this paper
• Emerging role of metabolic reprogramming in tumor immune evasion and immunotherapy

  2020cites this paper
• Activation of Adenosine Monophosphateâ•flActivated Protein Kinase Reduces the Onset of Dietâ•’Induced Hepatocellular Carcinoma in Mice

  2020cites this paper
• HSF1/AMPKα2 mediated alteration of metabolic phenotypes confers increased oxaliplatin resistance in HCC cells.

  2019cites this paper
• A study on the efficacy of recombinant human endostatin combined with apatinib mesylate in patients with middle and advanced stage non-small cell lung cancer.

  2019cites this paper
• Mechanism of Activation of AMPK/P53-CyPD Signaling Pathway in Inhibiting Osteoblast Apoptosis Induced by Dexamethasone

  2019cites this paper
• A study on features and markers of cellular metabolic rewiring

  2019cites this paper
• Combination of the natural product capsaicin and docetaxel synergistically kills human prostate cancer cells through the metabolic regulator AMP-activated kinase

  2019cites this paper
• Metformin Use and Lung Cancer Risk in Diabetic Patients: A Systematic Review and Meta-Analysis

  2019cites this paper
• CD147‑mediated reprogrammed glycolytic metabolism potentially induces immune escape in the tumor microenvironment (Review).

  2019influential citation
• Metformin Inhibit Lung Cancer Cell Growth and Invasion in Vitro as Well as Tumor Formation in Vivo Partially by Activating PP2A

  2019cites this paper
• Salicylate enhances the response of prostate cancer to radiotherapy

  2019cites this paper
• A New Method for Ethical and Efficient Evidence Generation for Off-Label Medication Use in Oncology (A Case Study in Glioblastoma)

  2019cites this paper
• Overcoming platinum-acquired resistance in ovarian cancer patient-derived xenografts

  2019cites this paper
• Diosgenin Supplementation Prevents Lipid Accumulation and Induces Skeletal Muscle-Fiber Hypertrophy in Rats.

  2019cites this paper
• A Genome-wide Survey, Model Selection, Phylogenetic Analysis and Protein-protein Interactional Network Profile of the Metazoan PRKAG Genes from 22 Vertebrate Genomes

  2019cites this paper
• Phyotochemical candidates repurposing for cancer therapy and their molecular mechanisms.

  2019cites this paper
• Gentisic Acid, a Quinonoid Aspirin Metabolite in Cancer Prevention and Treatment. New Horizons in Management of Brain Tumors and Systemic Cancers

  2018cites this paper
• Regulatory interactions between long noncoding RNA LINC00968 and miR-9-3p in non-small cell lung cancer: A bioinformatic analysis based on miRNA microarray, GEO and TCGA.

  2018cites this paper
• Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells

  2018cites this paper
• Knockdown of AMPKα decreases ATM expression and increases radiosensitivity under hypoxia and nutrient starvation in an SV40-transformed human fibroblast cell line, LM217.

  2018cites this paper
• 18F-Flortanidazole Hypoxia PET Holds Promise as a Prognostic and Predictive Imaging Biomarker in a Lung Cancer Xenograft Model Treated with Metformin and Radiotherapy

  2018cites this paper
• Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

  2018cites this paper
• Metformin's antitumour and anti‐angiogenic activities are mediated by skewing macrophage polarization

  2018cites this paper
• The role of compartmentalized signaling pathways in the control of mitochondrial activities in cancer cells.

  2018cites this paper
• Activation of AMPK by simvastatin inhibited breast tumor angiogenesis via impeding HIF‐1α‐induced pro‐angiogenic factor

  2018cites this paper
• Oxidative stress regulates cellular bioenergetics in esophageal squamous cell carcinoma cell

  2017cites this paper
• Sensing and responding to energetic stress: Evolution of the AMPK network.

  2017cites this paper
• Statistically controlled identification of differentially expressed genes in one-to-one cell line comparisons of the CMAP database for drug repositioning

  2017cites this paper
• 18 F-HX4 Hypoxia PET Holds Promise as a Prognostic and Predictive Imaging Biomarker in a Lung Cancer Xenograft Model Treated with Metformin and Radiotherapy

  year unknowncites this paper