Genetic insight and therapeutic targets in squamous-cell lung cancer

Abstract

Squamous-cell lung cancer is one of the most prevalent subtypes of lung cancer worldwide and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 gene and mutations of the discoidin domain receptor 2 gene as potential novel targets for the treatment of squamous-cell lung cancer patients. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.Oncogene ( Keywords: squamous-cell lung cancer; FGFR1; DDR2 Major advances in molecular biology and high-throughput sequencing techniques have boosted cancer drug treatment strategies over the past decades. 1 --6 The envisioned paradigm is the identification of genetic aberrations that are unique for defined subgroups of patients, and the development of drugs that specifically aim at oncogenic targets and their signaling pathways of these patients. In lung cancer, this development has led to the identification of oncogenic EGFR mutations that are present in up to 20% of adenocarcinoma patients 7 --9 and confer exquisite sensitivity to EGFR inhibitors (for example, gefitinib, erlotinib). 10 --12 Another example is the identification of EML4-ALK, the first fusion gene that is causally linked with the development of lung cancer. 13 Encouraging first clinical studies show that in patients with EML4 --ALK fusions overall response rates of up to 57% can be observed when treated with crizotinib. 14 However, the known 'druggable' targets are primarily enriched in the subgroup of adenocarcinomas of never smokers. 15 In addition, molecularly targeted therapeutics such as erlotinib, gefitinib and cetuximab, as well as conventional chemotherapeutics such as pemetrexed are poorly active in squamous-cell lung cancer patients. 11,16 Drugs such as bevacizumab or sorafenib that primarily inhibit vascular endothelial growth factor receptor (VEGFR) signaling are also not registered for the treatment of squamous-cell lung cancer patients due to increased risk of fatal hemorrhage. 17,18 Thus, the therapeutic repertoire for squamouscell lung cancer patients is rather limited.Several genomic studies tackled this unmet medical need by systematically characterizing the landscape of genetic lesions of squamous-cell lung cancer patients in order to define new therapeutically amenable targets. The first large-scale analysis of significant copy-number changes in squamous-cell lun...

Integration of genomic data analysis for demonstrating potential targets in the subgroup populations of squamous cell lung cancer patients

“…In summary, our analysis showed that a shorter smoking history and central localization of SCC tumors were related to a better survival outcome (Clus 1); while a long smoking history and peripheral distribution of tumors appeared to associate with a poor survival (Clus 2). Furthermore, our findings about the associations between survival outcomes and clinical factors in SCC patients are consistent with previous reports [24][25][26][27]. Moreover, statistical analysis on tobacco consuming history and initial age of diagnosis indicated that the old people with a long smoking history are more vulnerable.…”

“…There were 10 genes with a false discovery rate (FDR) Q value less than 0.1, including TP53, CDKN2A, PTEN, PIK3CA, KEAP1, MLL2, HLA-A, NFE2L2, NOTCH1, and RB1. The mutation rates of genes characterized previously in SCC (AKT1, DDR2, EGFR, BRAF, MET) [24] were also listed in the Figure 5A. Most of genes had missense mutation, which may result in changes in a coding sequence.…”

“…These genes were also reported as genetic alterations in SCC in previous works [14,[24][25][26][27]. We then further analyzed the expression and methylation of those genes.…”

KRAS Mutation in Small Cell Lung Carcinoma and Extrapulmonary Small Cell Cancer

“…In lung adenocarcinoma, KRAS mutations are more common in smokers (12)(13)(14)(15)(16). The prognostic significance of KRAS mutations in NSCLC is controversial (17)(18)(19).…”

Molecular Profiling in Non–Small Cell Lung Cancer: A Step Toward Personalized Medicine

“…There is a dire need to further clarify and identify additional driver oncogenes in squamous cell carcinoma and other subtypes (including small cell lung cancers and other rare neoplasms of the lung) in order to identify amenable therapeutic targets for these patients. 81 EPIGENETIC CHANGES Gene promoter methylation, histone modification, and regulation by microRNAs are the 3 common epigenetic phenomena, that indirectly influence the process of carcinogenesis by modulating gene mutation and expression. Aberrant DNA methylation is a well-studied mechanism for the inactivation of tumor suppressor genes.…”