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

Induction of tumor cell senescence may explain the response of a patient with BRAF kinase–impaired lung cancer to the multikinase inhibitor dasatinib. 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. During a clinical trial of the tyrosine kinase inhibitor dasatinib for advanced non–small cell lung cancer (NSCLC), one patient responded dramatically and remains cancer-free 4 years later. A comprehensive analysis of his tumor revealed a previously undescribed, kinase-inactivating BRAF mutation (Y472CBRAF); no inactivating BRAF mutations were found in the nonresponding tumors taken from other patients. Cells transfected with Y472CBRAF exhibited CRAF, MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase), and ERK (extracellular signal–regulated kinase) activation—characteristics identical to signaling changes that occur with previously known kinase-inactivating BRAF mutants. Dasatinib selectively induced senescence in NSCLC cells with inactivating BRAF mutations. Transfection of other NSCLC cells with these BRAF mutations also increased these cells’ dasatinib sensitivity, whereas transfection with an activating BRAF mutation led to their increased dasatinib resistance. The sensitivity induced by Y472CBRAF was reversed by the introduction of a BRAF mutation that impairs RAF dimerization. Dasatinib inhibited CRAF modestly, but concurrently induced RAF dimerization, resulting in ERK activation in NSCLC cells with kinase-inactivating BRAF mutations. The sensitivity of NSCLC with kinase-impaired BRAF to dasatinib suggested synthetic lethality of BRAF and an unknown dasatinib target. Inhibiting BRAF in NSCLC cells expressing wild-type BRAF likewise enhanced these cells’ dasatinib sensitivity. Thus, the patient’s BRAF mutation was likely responsible for his tumor’s marked response to dasatinib, suggesting that tumors bearing kinase-impaired BRAF mutations may be exquisitely sensitive to dasatinib. Moreover, the potential synthetic lethality of combination therapy including dasatinib and BRAF inhibitors may lead to additional therapeutic options against cancers with wild-type BRAF.