[ 18 F]FLT-PET as predictive non-invasive biomarker for neoadjuvant therapy with Wee1 and ATR inhibitors

ABSTRACT Besides immunotherapy, inhibitors of the DNA damage response (DDR) are currently one of the most promising contributors to improved cancer therapy. They exploit elevated replicative stress in cancer cells and often rely on synthetic lethality with existing gene deficiencies or between targeted pathways. In view of the absence of reliable histological biomarkers for replicative stress, this study examined [ 18 F]-fluorothymidine (FLT) positron emission tomography (PET) as alternative or complementary approach to predict treatment response to DDR inhibitors. Using orthotopic and syngeneic triple negative breast cancer mouse models and treatment with combined AZD6738 and AZD1775 (inhibiting ATR and Wee1, respectively) this study found that: a) Sequential [ 18 F]FLT-PET in the early phase of treatment was able to predict ATR/Wee1 inhibitor treatment efficacy, whereas b) [ 18 F]FLT tumor uptake at onset of therapy was unable to predict treatment outcome, despite c) [ 18 F]FLT tumor uptake positively correlating with Ki-67 staining, the clinically used proliferation marker. Importantly, non-invasive monitoring of changes in tumor biology by [ 18 F]FLT-PET predicted which tumor model responds to combined AZD6738/AZD1775 treatment and established a quantitative correlation in [18F]FLT tumor uptake with tumor shrinkage in individual responders. Since the inhibitors AZD6738 and AZD1775 are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic. To our knowledge this is the first study to correlate non-invasive PET imaging with treatment efficacy of DDR inhibitors. Graphical Abstract