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.

Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases

“…255 Although some of these clinical results were not definitive, the therapeutic clinical potential of Metformin is still worth exploring. 256 In the drug discovery process, natural products play a more important role than synthetic compounds, since natural products have enormous scaffold diversity and structural complexity. 257 Synthetic compounds may have weak biological activity compared to the natural products/parent compounds.…”

“…A phase IV clinical trial (NCT01247870) of Metformin in COPD exacerbations concluded that Metformin is unlikely to be beneficial as an acute treatment for COPD exacerbations in nondiabetic patients 255 . Although some of these clinical results were not definitive, the therapeutic clinical potential of Metformin is still worth exploring 256 . In the drug discovery process, natural products play a more important role than synthetic compounds, since natural products have enormous scaffold diversity and structural complexity 257 .…”

Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer

“…In vivo studies show that metformin treatment can inhibit the activation of various tyrosine kinase receptors (EGFR, IGFR and VEGFR) and the phosphorylation of mTOR through AMPK-dependent and independent mechanisms, thus inhibiting the occurrence and metastasis of lung cancer [ 10 , 11 ]. Metformin has also been shown to inhibit epithelial-mesenchymal transformation (EMT) and inhibit the proliferation of tumor cells [ 12 ]. It is noteworthy that metformin could amplify cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells [ 13 ].…”

Advances in Non-Small Cell Lung Cancer (NSCLC) Treatment—A Paradigm Shift in Oncology

“…Through the genetic modification of a patient’s own T cells to express a receptor targeting specific cancer antigens, CAR-T therapy has demonstrated ground-breaking success in haematological malignancies and is now being investigated for its potential in solid tumours [ 19 ]. Novel approaches such as inhalation therapy [ 20 ], improving drug solubility for delivery [ 21 ] and drug repurposing [ 20 , 22 ] are discussed in Review articles in this Special Issue. The promise of drug repurposing and combination therapy was demonstrated by Barrious-Bernal et al [ 23 ], in which Metformin, an anti-diabetic drug, when combined with EGFR TKI-Afatinib, demonstrated additive to synergic anti-tumour effects in TKI-resistant lung cancer cells.…”