Editors' ChoiceCancer

A Death by a Thousand Cuts

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Science Translational Medicine  27 Jul 2011:
Vol. 3, Issue 93, pp. 93ec119
DOI: 10.1126/scitranslmed.3002968

Lung cancer globally is the number one cause of cancer death in men in both developed and underdeveloped countries, with 70% of patients initially diagnosed with incurable disease. Like many other cancers, lung cancer is not a single entity but a tapestry of many diseases with different histology and molecular profiles.

The successful identification of the molecular aberrations in lung cancer has led to therapies that produce profound clinical responses in those patients with lung cancer harboring echinoderm microtubule-associated protein-like–anaplastic lymphoma kinase (EML-ALK) translocations or bearing epidermal growth factor receptor (EGFR) mutations. These subtypes make up less than 14% of all lung cancers, but our successes have profoundly changed how we approach the patients with these types of cancer.

A recent paper by Hammond et al. suggests that another molecular subtype of lung cancer will benefit from an existing molecular therapy—the drug dasatinib. The investigators sequenced over 201 genes, including the entire tyrosine kinome, in 20 primary squamous-cell lung cancer (SCC) samples and matched normal controls. They identified 25 missense mutations and, with further analysis of another 48 SCC samples, identified the discoidin domain receptor 2 (DDR2) kinase as the most common recurrent mutation in both samples subsets, a total of 3.8%. Silencing of mutated DDR2 with RNA interference in SCC cell lines caused cell death. They also discovered that lung cancer from a patient who had been in a dasatinib study and had responded bore a DDR2 mutation. Further, xenografts established from a DDR2 mutant cell line in mice showed sensitivity to dasatinib, and expression of mutated DDR2 led to cellular transformation that was blocked by dasatinib.

Larger studies looking at the effect of dasatinib in lung cancer patients with known DDR2 mutations are currently being planned. If these are positive, this study will have initiated another small but significant strike at a lung cancer.

P. S. Hammerman et al., Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 1, 78–89 (2011). [Abstract]

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