Potential Therapeutic Targets Are Identified in Lung Squamous Cell Cancers

Targeted agents, such as EGF receptor (EGFR) and anaplastic lymphoma kinase inhibitors, are now commonly used for the treatment of lung adenocarcinoma, the most common form of lung cancer, but no targeted therapy has been specifically developed for the second most common type of lung cancer, squamous cell carcinoma (SQCC). To gain insight into the etiology of these less characterized lung cancers and identify potential therapeutic targets, The Cancer Genome Atlas (TCGA) Research Network performed integrative genomic profiling of 178 previously untreated lung SQCCs. Compared with other tumor types analyzed as part of the TCGA, lung SQCCs had a high mutation rate and a high number of copy number alterations. TP53 mutations were found in more than 80% of lung SQCCs, and CDKN2A, which encodes the tumor suppressors p16^INK4A and p14^ARF, was mutationally or epigenetically inactivated in 72% of tumors. Other recurrently mutated genes affected PI3K signaling (47% of tumors), squamous cell differentiation (44% of tumors), and oxidative stress response (34% of tumors) pathways. No recurrent gene fusions were identified. Unlike lung adenocarcinomas, KRAS and EGFR mutations were extremely rare, and the spectrum of the few lung SQCC EGFR mutations differed from those observed in lung adenocarcinoma. Although targeting these pathways may not be effective in the vast majority of lung SQCCs, almost every SQCC had at least one potentially actionable mutation in a receptor, kinase, or other type of signaling molecule. Furthermore, many lung SQCCs had somatic alterations in genes targetable by therapeutic agents that are approved or in clinical trials. The genomic characterization of SQCC thus has the potential to guide the specific development of targeted therapies for this particular type of lung cancer.

The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012 Sept 9 [Epub ahead of print].