Metabolic targeting, immunotherapy and radiation in locally advanced non-small cell lung cancer: Where do we go from here?

Abstract

In the US, there are ~250,000 new lung cancer diagnoses and ~130,000 deaths per year, and worldwide there are an estimated 1.6 million deaths per year from this deadly disease. Lung cancer is the most common cause of cancer death worldwide, and it accounts for roughly a quarter of all cancer deaths in the US. Non-small cell lung cancer (NSCLC) represents 80-85% of these cases. Due to an enormous tobacco cessation effort, NSCLC rates in the US are decreasing, and the implementation of lung cancer screening guidelines and other programs have resulted in a higher percentage of patients presenting with potentially curable locoregional disease, instead of distant disease. Exciting developments in molecular targeted therapy and immunotherapy have resulted in dramatic improvement in patients’ survival, in combination with new surgical, pathological, radiographical, and radiation techniques. Concurrent platinum-based doublet chemoradiation therapy followed by immunotherapy has set the benchmark for survival in these patients. However, despite these advances, ~50% of patients diagnosed with locally advanced NSCLC (LA-NSCLC) survive long-term. In patients with local and/or locoregional disease, chemoradiation is a critical component of curative therapy. However, there remains a significant clinical gap in improving the efficacy of this combined therapy, and the development of non-overlapping treatment approaches to improve treatment outcomes is needed. One potential promising avenue of research is targeting cancer metabolism. In this review, we will initially provide a brief general overview of tumor metabolism as it relates to therapeutic targeting. We will then focus on the intersection of metabolism on both oxidative stress and anti-tumor immunity. This will be followed by discussion of both tumor- and patient-specific opportunities for metabolic targeting in NSCLC. We will then conclude with a discussion of additional agents currently in development that may be advantageous to combine with chemo-immuno-radiation in NSCLC.

Unravelling the Triad of Lung Cancer, Drug Resistance, and Metabolic Pathways

“…KRAS is nearly exclusively seen in adenocarcinomas, while TP53 is the most frequently mutated gene in non-small cell lung cancers (NSCLCs). RAF-MEK-MAPK and PI3K-Akt-mTOR are the two signalling pathways that are most frequently altered in lung cancer [81]. TP53 is mutated in 46% of NSCLC tumours.…”

Unravelling the Triad of Lung Cancer, Drug Resistance, and Metabolic Pathways

“…Further, there is enhanced gly-colysis and glucose transport attributed to the upregulation of phosphoglucomutase (PGM). Additionally, TP53 is no longer capable of inhibiting the activity of glucose 6 phosphate dehydrogenase (G6PD) [82]. In addition to controlling glucose levels, the PI3K-Akt-mTOR signal transduction pathway triggers cancerous mutations that have a variety of negative side effects, including angiogenesis, proliferation, and differentiation.…”