| 18056475 |
Solit DB, Santos E, Pratilas CA, Lobo J, Moroz M, Cai S, Blasberg R, Sebolt-Leopold J, Larson S, Rosen N: 3'-deoxy-3'-[18F] fluorothymidine positron emission tomography is a sensitive method for imaging the response of BRAF-dependent tumors to MEK inhibition. Cancer Res. 2007 Dec 1;67(23):11463-9.
Activating mutations of BRAF occur in approximately 7% of all human tumors and in the majority of melanomas. These tumors are very sensitive to pharmacologic inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), which causes loss of D-cyclin expression, hypophosphorylation of Rb, and G (1) arrest. Growth arrest is followed by differentiation or senescence and, in a subset of BRAF mutant tumors, by apoptosis. The former effects result in so-called "stable disease" and, in patients with cancer, can be difficult to distinguish from indolent tumor growth. The profound G (1) arrest induced by MEK inhibition in BRAF mutant tumors is associated with a marked decline in thymidine uptake and is therefore potentially detectable in vivo by noninvasive 3'-deoxy-3'-[(18) F] fluorothymidine ([(18) F] FLT) positron emission tomography (PET) imaging. In SKMEL-28 tumor xenografts, MEK inhibition completely inhibited tumor growth and induced differentiation with only modest tumor regression. MEK inhibition also resulted in a rapid decline in the [(18) F] FLT signal in V600E BRAF mutant SKMEL-28 xenografts but not in BRAF wild-type BT-474 xenografts. The data suggest that [(18) F] FLT PET can effectively image induction of G (1) arrest by MEK inhibitors in mutant BRAF tumors and may be a useful noninvasive method for assessing the early biological response to this class of drugs. |
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