by ecancer reporter Clare Sansom

Lung cancer is the leading cause of cancer death in many developed countries. It is a complex, heterogeneous disease that is divided into a number of histological subtypes, the most important being the distinction between small cell and non-small cell lung cancer (NSCLC). About a quarter of all lung cancers are classified as squamous cell carcinoma (SCC) of the lung.

This NSCLC subtype is much less likely than the other main NSCLC subtype, adenocarcinoma, to respond to treatment with EGFR kinase inhibitors such as gefitinib and erlotinib. Several other promising drug targets for NSCLC have been discovered, but these, again, seem to be more useful for adenocarcinoma.

Until very recently, little was known about the mutations driving SCC of the lung and consequently of its most appropriate drug targets. A large group of researchers led by Matthew Meyerson of Dana-Farber Cancer Institute, Boston, Massachusetts, USA, Roman Thomas of the Max Planck Institute of Neurobiology, Cologne, Germany and Eric Haura, H. Lee Moffitt Cancer Center, Tampa, Florida, USA has now sequenced the tyrosine kinase component of the SCC genome in order to identify novel mutations and novel therapeutic targets for this disease.

The researchers used the Sanger method to sequence 201 genes, including all known tyrosine kinases, in an initial set of twenty samples of lung squamous cell carcinomas and matched healthy lung tissue from the same patients. Somatic mis-sense mutations were identified in six tyrosine kinase genes in this set; these genes were sequenced in a further 48 samples including two SCC cell lines.

This led to the identification of the gene discoidin domain receptor 2 (DDR2) as the most frequently mutated kinase in both screens. Sequencing this gene in a further 222 tumours revealed mutations in 11 of 290 (3.8%) total samples, falling to nine of 277 (3.2%) when cell lines were excluded. Most mutations were observed in highly conserved regions of the gene and no significant differences were noted in either its copy number or its expression pattern.

In order to investigate the significance of DDR2 as a potential drug target for this disease, the researchers tested a number of SCC cell lines with DDR2 mutations with tyrosine kinase inhibitors known to be active against the gene product.

These include imatinib and dasatinib, which have current FDA approval as anti-cancer drugs.  Cell lines bearing DDR2 mutations were sensitive to these drugs, particularly dasatinib, but others bearing KRAS mutations only were not. Furthermore, tumour cells carrying DDR2 mutations could be selectively killed by RNAi knockdown of this gene, and cell lines in which the “gatekeeper” DDR2 mutation T790M had been introduced became less responsive to dasatinib.

The researchers then injected nude mice with SCC cell lines both with and without mutations in DDR2. Only tumours derived from the two cell lines bearing the DDR2 mutation were sensitive to treatment with dasatinib.

All mutations discovered in SCC cells were determined to be gain-of-function mutations, clearly identifying this gene as an oncogene in this tumour type; cell lines bearing mutations in this gene were also found to maintain Src phosphorylation and to be particularly sensitive to compounds – such as dasatinib – that are active against both these kinases. 

As dasatinib is already in clinical use, it is relatively easy to test its potential in further indications through clinical trials, and, in fact, early phase trials of this drug in advanced lung cancer are in progress.

The researchers identified one of seven lung cancer patients in a small trial who had responded very well to combination therapy with dasatinib and erlotinib. Sequencing of tumour tissue from this patient revealed a mutation in the kinase domain of DDR2, S768R, which had not been seen in any of the samples previously tested. However, it was impossible to identify this as a somatic mutation as no matched normal tissue was available.

Taken together, these results suggest that targeted clinical trials with dasatinib and other kinase inhibitors known to be active against DDR2 should prove a useful strategy for improving the treatment options for at least a small minority of patients with this intractable disease.

Reference

Peter S. Hammerman, P.S., Sos, M.L. and Ramos, A.H. (2011). Mutations in the DDR2 Kinase Gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discovery 1(1), 78-89. doi:10.1158/2159-8274.CD-11-0005