18F-FLT PET, a Non-Invasive 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 (CDKs) is a proven therapeutic strategy in treating HR+/HER2- breast cancer and a variety of other cancers. 18F-FLT (18F-3'-deoxy-3'-fluorothymidine) is a validated positron emission tomography (PET) biomarker to measure cell proliferation. Here we show the utility of 18F-FLT PET imaging as a pharmcodynamic (PD) 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 immunohistochemistry (IHC) biomarkers of tumor cell proliferation (Ki67 and pRb) were evaluated for correlation. Tumor growth inhibition (TGI) studies demonstrated that Palbociclib was efficacious in MCF7 model, but not in OVCAR-3 model, whereas PF-07104091 showed dose-dependent TGI 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 OVCAR-3 model. In contrast, 18F-FLT PET biomarker showed reduced uptake in MCF7 model after treatment with both Palbociclib and PF-07104091. Similarly, PF-07104091 demonstrated reduced 18F-FLT uptake in the NIBR-5493, an ovarian cancer PDX 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, non-invasive 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 identifying responding and non-responding patients.