18F-FLT PET, a Noninvasive Pharmacodynamic Biomarker of Tumor Cell Proliferation, Detected Differential Response to Various Cyclin-Dependent Kinase (CDK) Inhibitors.

Abstract

A dysregulated cell cycle is a hallmark of cancer and inhibition of cyclin-dependent kinases (CDK) is a proven therapeutic strategy in treating hormone receptor-positive/HER2- breast cancer and a variety of other cancers. 18F-3'-deoxy-3'-fluorothymidine (18F-FLT) is a validated PET biomarker to measure cell proliferation. In this study, we show the utility of 18F-FLT PET imaging as a pharmcodynamic biomarker in differentiating the efficacy of PF-07104091 (CDK2-selective inhibitor) in palbociclib (CDK4/6 inhibitor)-sensitive and -resistant tumor models. 18F-FLT PET imaging was performed after 4 days of treatment with CDK inhibitors and IHC biomarkers of tumor cell proliferation (Ki67 and pRb) were evaluated for correlation. Tumor growth inhibition studies demonstrated that palbociclib was efficacious in an MCF7 model but not in an OVCAR-3 model, whereas PF-07104091 showed dose-dependent tumor growth inhibition in both MCF7 and OVCAR-3 models. Consistent with this observation, 18F-FLT PET was able to differentiate the resistance to palbociclib from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in the OVCAR-3 model. In contrast, the 18F-FLT PET biomarker showed reduced uptake in the MCF7 model after treatment with both palbociclib and PF-07104091. Similarly, PF-07104091 demonstrated reduced 18F-FLT uptake in NIBR-5493, an ovarian cancer patient-derived xenograft model. IHC biomarkers Ki67 and pRb correlated with the 18F-FLT uptake trends in all three tumor models. This work highlights the utility of 18F-FLT PET as a quantitative, noninvasive biomarker which provides whole-body information. 18F-FLT PET has potential to be a biomarker in novel CDK inhibitor clinical trials to evaluate palbociclib resistance and to identify responding and nonresponding patients.