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3'-Deoxy-3'-[¹⁸F]Fluorothymidine Positron Emission Tomography Is a Sensitive Method for Imaging the Response of BRAF-Dependent Tumors to MEK Inhibition

Departments of ¹ Medicine, ² Radiology, ³ Pediatrics, and ⁴ Molecular Pharmacology and Chemistry and ⁵ Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York and ⁶ Pfizer Global Research and Development, Ann Arbor, Michigan

Requests for reprints: Neal Rosen, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 646-888-2075; E-mail: rosenn{at}mskcc.org.

Activating mutations of BRAF occur in 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 G₁ 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 G₁ 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'-[¹⁸F]fluorothymidine ([¹⁸F]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 [¹⁸F]FLT signal in V600E BRAF mutant SKMEL-28 xenografts but not in BRAF wild-type BT-474 xenografts. The data suggest that [¹⁸F]FLT PET can effectively image induction of G₁ 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. [Cancer Res 2007;67(23):11463–9]

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