Molecular links between COPD and lung cancer: new targets for drug discovery?

ABSTRACT

Introduction: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation.

Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer.

Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.

KEYWORDS:

• COPD
• lung cancer
• smoking
• squamous cell carcinoma

Article highlights

• COPD and lung cancer share common risk factors represented by smoke exposure and genetic predisposition but only a proportion of lifelong smokers will develop COPD and lung cancer.

• Smoking behavior in susceptible patients causes genetic and epigenetic alterations, mitochondria dysfunction and oxidative stress, and alteration of immune response.

• COPD is likely a driver of lung cancer, by increasing oxidative stress and resulting DNA damage, chronic exposure to proinflammatory cytokines, repression of the DNA repair mechanisms and increased cellular proliferation.

• Persistent chronic airway inflammations with several pathways of activation are processes that link COPD and lung cancer.

• Defective innate immune responses in COPD provide an environment conducive to the onset of carcinogenesis.

• Combining risk models of lung cancer and COPD with molecular phenotyping of young and ‘healthy smokers’ are essential to identify molecular targets for new therapies.

• Combined experimental models of COPD and lung cancer may provide a better model of human lung cancer.

This box summarizes the key points contained in the article.

Declaration of interest

The Authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

PM Hansbro is funded by a Fellowship from the National Health and Medical Research Council of Australia [1079187]. S Mumby and IM Adcock were supported by the British Heart Foundation [PG/14/27/30679] and the Dunhill Medical Trust [R368/0714]. IM Adcock was also supported by the Wellcome Trust [093080/Z/10/Z].