Will We Unlock the Benefit of Metformin for Patients with Lung Cancer? Lessons from Current Evidence and New Hypotheses

Abstract

Metformin has been under basic and clinical study as an oncological repurposing pharmacological agent for several years, stemming from observational studies which consistently evidenced that subjects who were treated with metformin had a reduced risk for development of cancer throughout their lives, as well as improved survival outcomes when diagnosed with neoplastic diseases. As a result, several basic science studies have attempted to dissect the relationship between metformin's metabolic mechanism of action and antineoplastic cellular signaling pathways. Evidence in this regard was compelling enough that a myriad of randomized clinical trials was planned and conducted in order to establish the effect of metformin treatment for patients with diverse neoplasms, including lung cancer. As with most novel antineoplastic agents, early results from these studies have been mostly discouraging, though a recent analysis that incorporated body mass index may provide significant information regarding which patient subgroups might derive the most benefit from the addition of metformin to their anticancer treatment. Much in line with the current pipeline for anticancer agents, it appears that the benefit of metformin may be circumscribed to a specific patient subgroup. If so, addition of metformin to antineoplastic agents could prove one of the most cost-effective interventions proposed in the context of precision oncology. Currently published reviews mostly rely on a widely questioned mechanism of action by metformin, which fails to consider the differential effects of the drug in lean vs. obese subjects. In this review, we analyze the pre-clinical and clinical information available to date regarding the use of metformin in various subtypes of lung cancer and, further, we present evidence as to the differential metabolic effects of metformin in lean and obese subjects where, paradoxically, the obese subjects have reported more benefit with the addition of metformin treatment. The novel mechanisms of action described for this biguanide may explain the different results observed in clinical trials published in the last decade. Lastly, we present novel hypothesis regarding potential biomarkers to identify who might reap benefit from this intervention, including the role of prolyl hydroxylase domain 3 (PHD3) expression to modify metabolic phenotypes in malignant diseases.

Keywords: EGFR; PHD3; body mass index; fatty acid oxidation; metformin.

Figure 1

Metformin effects on non-transformed cells versus lung cancer cells. Metformin treatment has different effects on LC cells than non-transformed cells. In both cell types, metformin exerts its effect through a dysfunction of complex I of the electron transport chain, however, in non-transformed cells, metformin promotes glucose incorporation through increased expression of GLUT1 (green membrane proteins), hexokinases (orange circles), and decreasing the gluconeogenesis process. The ATP generation process is also increased through activation of AMPK and with a sustained OXPHOS. In LC cells, metformin stimulates energy generation through over-activation of OXPHOS processes associated with an increasing of AMPK pathway activity, mTOR inhibition, and a decrease in all glycolytic proteins and processes that are associated with this metabolic pathway. (Created with BioRender.com).

Figure 2

Metformin effects in the interplay between EGFR, IGFR, and AMPK pathways. Mutated EGFR and IGF pathways can increase PI3K activity, through activation of PKB/AKT, stimulating the rest of the pathway, and, also, these kinases can promote the glycolytic cell phenotype through HIF1α expression by the stimulation of mTOR and its downstream effectors. This effect promotes the translocation and increasing the expression of GLUT1 and HKs, giving cells a greater glycolytic potential. When metformin treatment is incorporated by OCTs, it can inhibit mTOR activity through AMPK activation, increasing TSC2/RHEB function, and these processes can attenuate protein synthesis that is promoted by mTOR and its effectors. LKB1 can also increase its activity through calcium-dependent processes or through the influence of SIRT1. LKB1 activation leads to increased AMPK activity associated with an inhibition of membrane EGFR and IGFR activity, and metformin has also shown direct inhibition of expression of both transmembrane receptors. (Created with BioRender.com).