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

Autores organización

• 

  Andres Felipe Cardona Mendoza

  Autor

  acardonam@unbosque.edu.co

Autores

• Barrios-Bernal P
• Zatarain-Barrón ZL
• Hernández-Pedro N
• Orozco-Morales M
• Olivera-Ramírez A
• Ávila-Moreno F
• Colín-González AL
• Rosell R
• Arrieta O

Grupos de investigación

• Grupo de Inmunología celular y molecular Universidad El Bosque (InmuBo)

  Investigador

  Maria Consuelo Romero Sanchez

  romeromaria@unbosque.edu.co

Resumen

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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

• antineoplastic metal complex; epidermal growth factor receptor; hydroxymethylglutaryl coenzyme A reductase kinase; immune checkpoint inhibitor; metformin; protein tyrosine kinase inhibitor; sirtuin 1; somatomedin receptor; adjuvant therapy; antineoplastic activity; body mass; cancer adjuvant therapy; cancer combination chemotherapy; cancer epidemiology; cancer patient; cancer radiotherapy; cancer risk; cancer survival; cost effectiveness analysis; drug effect; drug mechanism; drug repositioning; evidence based medicine; gene; gene expression; genetic modification; human; hypothesis; lung cancer; non insulin dependent diabetes mellitus; non small cell lung cancer; nonhuman; obesity; oncology; personalized medicine; PHD3 gene; phenotype; randomized controlled trial (topic); regulatory mechanism; Review; risk reduction; signal transduction