Pharmacogenetics of platinum-based chemotherapy in non-small cell lung cancer: predictive validity of polymorphisms of ERCC1

ABSTRACT

Introduction: The efficacy of platinum-based chemotherapy for patients with non-small cell lung cancer (NSCLC) is limited by chemoresistance. Platinum drugs damage DNA by introducing intrastrand and interstrand crosslinks which result in cell death. Excision repair cross-complementing 1 (ERCC1) is a member of the nucleotide excision repair (NER) pathway which erases such defects. Single nucleotide polymorphisms (SNPs) in ERCC1 impair this activity and have been suggested to predict the response to chemotherapy.

Area covered: Among the polymorphisms of proteins involved in uptake, metabolism, cytotoxicity and efflux of platinum drugs, codon 118 C/T and C8092A in ERCC1 are the best characterized SNPs studied for their predictive power. Here, the divergent results for studies of these markers in NSCLC are summarized and the reasons for this contradictory data discussed.

Expert opinion: Cytotoxicity of platinum compounds comprise complex cellular processes for which DNA repair may not constitute the rate limiting step. These drugs are administered as doublets to histologically diverse patients and, furthermore, the NER pathway in ERCC1 wildtype cohorts may be still impaired by the chemotherapeutics applied. At present, assessment of a limited number of polymorphism in DNA repair proteins is not reliably associated with response to treatment in NSCLC patients.

KEYWORDS:

• Non-small cell lung cancer
• cisplatin
• ERCC1
• polymorphism
• drug response

Article highlights

• Platinum-based chemotherapy for NSCLC patients is limited by chemoresistance

• ERCC1-mediated NER DNA repair is involved in failure of therapy

• ERCC1 activity is impaired by 118 C/T and C8092A polymorphisms

• A large number of studies yielded contradictory results for the predictive power of the ERCC1 polymorphisms

• Studies involved heterogenous cohorts and different chemotherapy doublet regimen

• ERCC1 wildtype patients seem to have inactivated NER due to added chemotherapeutics

Polymorphisms in ERCC1 lack significant predictive power in NSCLC patients

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. Peer reviewers on this manuscript have nothing to disclose.

Additional information

Funding

This paper was not funded.