Research ArticleCancer

Kinase-Impaired BRAF Mutations in Lung Cancer Confer Sensitivity to Dasatinib

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Science Translational Medicine  30 May 2012:
Vol. 4, Issue 136, pp. 136ra70
DOI: 10.1126/scitranslmed.3003513

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A Lucky Break with BRAF

The prognosis for those with metastatic non–small cell lung cancer (NSCLC) is bleak—the median survival time is measured in months. Therapeutic benefits have been achieved with targeted drugs in subpopulations of NSCLC patients with specific mutations, but the genetic changes responsible for this disease are undefined in most cases. Understanding why certain tumors respond to a given treatment might help determine useful therapeutic targets. Sen et al. now describe a striking case—the mutation responsible for the strong response of one patient with metastatic NSCLC to treatment with the tyrosine kinase inhibitor dasatinib.

In a previous clinical trial of dasatinib treatment for metastatic NSCLC that lasted for 12 weeks, only a single patient responded to treatment; his tumor shrank and continued to shrink after treatment ended. Four years later, he appears free of active cancer. The researchers analyzed this patient’s tumor tissue and did not detect mutations that had been associated with NSCLC in other patients, but did find a mutation in the serine-threonine kinase BRAF that markedly impaired its kinase activity. (In contrast, another well-characterized oncogenic mutation in BRAF is kinase-activating.) Sen et al. found that in NSCLC cell lines with other kinase-inactivating BRAF mutations, dasatinib induced largely irreversible senescence—cell cycle arrest. Overexpression of kinase-active BRAF, however, increased dasatinib resistance in these cells, indicating that the inactive BRAF kinase was required for their dasatinib sensitivity. Furthermore, treatment of dasatinib-resistant cancer cells that express wild-type BRAF with a BRAF inhibitor increased their sensitivity to dasatinib.

Exactly how dasatinib induces senescence in NSCLC cells with kinase-impaired BRAF is not yet clear, but the finding opens new possibilities for treatment. Cancers in which BRAF is impaired may respond well to dasatinib; more broadly, dasatinib in combination with BRAF inhibitors may be useful for treating tumors that express wild-type BRAF.

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