68Ga-pAKTi PET/CT imaging as a non-invasive method to assess tumor response to PI3Kα Inhibitor in breast cancer

Abstract PI3K-AKT signaling is among the most attractive cancer therapeutic targets and the first PI3Kα inhibitor has been approved for breast cancer therapy and hundreds of clinical trials. However, how to predict or monitor tumor response to PI3Kα inhibitor in a non-invasive method remains challenging. Here, we developed a PET imaging probe 68Ga-pAKTi detecting phosphorylated-AKT to precisely assess breast tumor response to PI3Kα inhibitor non-invasively in vivo. Using triple negative breast cancer as model, 68Ga-pAKTi PET/CT imaging showed robust radioactive accumulation in PTEN lost or PIK3CA mutated tumors that hyper-phosphorylate AKT. Moreover, changes of 68Ga-pAKTi uptake upon short-term PI3Kα inhibition differentiated PIK3CA mutated tumors from PTEN lost tumors to predict long-term tumor response to PI3Kα inhibitor. Together, our 68Ga-pAKTi PET imaging visualized AKT phosphorylation in vivo, and accurately predicted tumor responses to PI3Kα inhibitor. This work supports future clinical trials using 68Ga-pAKTi PET/CT to optimize clinical implication of PI3K pathway drugs for cancer treatment.