Pharmacogenomics in the Treatment of Lung Cancer: an Update

Abstract

Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies.

On the pharmacogenetics of non-small cell lung cancer treatment

“…These data support a role of high EGFR expression in the intestinal lumen associated with the EGFR promoter polymorphism variants among the causes of diarrhea, as also reported by Rudin and collaborators [82]. However, diarrhea was also correlated with the ABCG2 421C/A variant: 44% of gefitinib-treated NSCLC patients heterozygous for ABCG2 421C/A presented this adverse effect [83]. Conversely, no correlation between gefitinib-induced toxicity and ABCG2 421C/A was found in a population of 94 Caucasian NSCLC patients, where moderate-severe diarrhea correlated with the ABCG2 15622C/T polymorphism and the ABCG2 (1143C/T, −15622C/T) haplotype [79].…”

“…This could be due to several issues about clinical and laboratory methodologies. [83,85] A frequent question concerns the way of considering the heterozygotes relatively to wild-type and variant homozygotes [17]. When the size of the population is large enough and when the functional effect of the polymorphism is not known, it is certainly better to analyze independently the three genotypes, with the assumption that each variant allele contributes to the phenotype.…”

“…Although the list of pharmacogenomic biomarkers in drug labeling include several drugs used for NSCLC (Table 2), and a number of important genetic determinants have been identified thus far in different tumor types, including NSCLC, the clinical relevance of most germ-line gene variants currently remains unconfirmed, and such data have not yet been translated into a better therapeutic management [83].…”

miR-215 suppresses proliferation and migration of non-small cell lung cancer cells

“…In recent years, high-throughput sequencing has provided effective tools to deeply investigate changes of genetics and epigenetics in the development of lung cancer (3). Targeting the molecular changes in lung cancer cannot only help to find effective treatments, but also play key role in risk assessment, early diagnosis, more accurate staging and typing, recurrence and prognosis assessment in lung cancer (4). …”

Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment

“…Cancer metastasis is a remarkably complex and multiparametric process, comprised of sequential stages that make up the so-called "metastatic cascade". 17 These stages include: (1) dissociation of cells from the primary tumor (shedding), (2) local invasion through the basement membrane and the extracellular matrix (ECM), (3) entry into the blood or lymphatic vessels (intravasation), (4) circulation through the lymphatic system and the bloodstream, (5) arrest in the capillaries and migration out of the vasculature (extravasation) into the secondary site (seeding), (6) formation of micro and macro-metastasis in the target organs, and (7) induction of new blood vessels (angiogenesis) that will provide oxygen and nutrients to the metastatic tumor 18 (Fig. 1A).…”