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

// Michael Troncone 5,* , Stephanie M. Cargnelli 5,* , Linda A. Villani 2,* , Naghmeh Isfahanian 1 , Lindsay A. Broadfield 2 , Laura Zychla 6 , Jim Wright 1,6 , Gregory Pond 1 , Gregory R. Steinberg 2,3 and Theodoros Tsakiridis 1,4,6 1 Department of Oncology, McMaster University, Hamilton, Ontario, Canada 2 Department of Biochemistry, Hamilton, Ontario, Canada 3 Department of Medicine, Hamilton, Ontario, Canada 4 Department of Pathology and Molecular Medicine, Hamilton, Ontario, Canada 5 DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada 6 Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, Ontario, Canada * These authors have contributed equally to this manuscript Correspondence to: Theodoros Tsakiridis, email: // Keywords : AMPK, ionizing radiation, stress, cell cycle, ATM Received : December 23, 2016 Accepted : March 19, 2017 Published : April 27, 2017 Abstract 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.