Pharmacogenomics of Cisplatin Sensitivity in Non-Small Cell Lung Cancer

Abstract

Cisplatin, a platinum-based chemotherapeutic drug, has been used for over 30 years in a wide variety of cancers with varying degrees of success. In particular, cisplatin has been used to treat late stage non-small cell lung cancer (NSCLC) as the standard of care. However, therapeutic outcomes vary from patient to patient. Considerable efforts have been invested to identify biomarkers that can be used to predict cisplatin sensitivity in NSCLC. Here we reviewed current evidence for cisplatin sensitivity biomarkers in NSCLC. We focused on several key pathways, including nucleotide excision repair, drug transport and metabolism. Both expression and germline DNA variation were evaluated in these key pathways. Current evidence suggests that cisplatin-based treatment could be improved by the use of these biomarkers.

On the pharmacogenetics of non-small cell lung cancer treatment

“…However, the risk of loss of heterozygosity may introduce a critical bias and alter the conclusions of a study dedicated, for instance, at the identification of the polymorphisms of a gene expressed in the liver and involved in drug activation or detoxification, such as cytidine deaminase for gemcitabine [19]. Conversely, it might be interesting to know the tumor as well as the germinal genotype of polymorphisms of DNA repair genes, because the DNA repair involved in resistance to alkylating drugs actually occurs within the cancer cells [20]. Of note, recent reports have shown that lung cancers can be characterized by substantial heterogeneity [21].…”

“…Furthermore, the interaction between genetic variations such as SNPs and copy number variations and somatic mutations in some of the tumor most important genes might affect response to specific anticancer drugs, and several studies correlated cisplatin and DNA damage and repair with TP53 mutations and p53 activity [29]. Many efforts have been therefore invested to identify pharmacogenetic biomarkers that can be used to predict sensitivity or resistance to cisplatin, including TP53 and DNA repair pathway genes [20]. However, the present review focuses on examples on how genetics might affect drug response of the conventional chemotherapeutic agent pemetrexed as well as of the anti-EGFR targeted agents gefitinib and erlotinib, as described in the following paragraphs.…”

Sox2 inhibits Wnt-β-catenin signaling and metastatic potency of cisplatin-resistant lung adenocarcinoma cells

“…However, the prognosis of this treatment in patients with aggressive NSCLC remains poor, mainly owing to the development of multidrug resistance, in particular against cisplatin regimens (6,7). Mechanistically, the cisplatin therapy induces DNA interstrand and intrastrand crosslinks in tumor cells, sequentially inhibiting cell replication and transcription (8).…”

The use of biomarkers in the treatment of non-small cell lung cancer

“…[68] There may be confounding factors such as the use of additional chemotherapeutic agents in these studies that make interpretation of the results difficult. [69] Other studies have looked at specific polymorphisms within the ERCC1 gene which are associated with increased ERCC1 mRNA levels and improved PFS compared with patients who were homozygous for ERCC1-C8092 (6.4 vs. 4.0 months; p = 0.001). Other studies have found a correlation between rs11615 polymorphism and ORR to cisplatin; however another study concluded there was no correlation.…”