Dynamic Ultrasound Molecular Targeted Imaging of Senescencein Evaluation of Lapatinib Resistance in HER2 Positive Breast Cancer

Prolonged treatment of HER2+ breast cancer cells with lapatinib (LAP) causes cellular senescence and acquired drug resistance, which often associating with poor prognosis for patients. We aim to explore the correlation between cellular senescence and LAP resistance in HER2+ breast cancer, screening for molecular marker of reversible senescence, and construct targeted nanobubbles for ultrasound molecular imaging and dynamically evaluate LAP resistance. In this study, we established a new cellular model of reversible cellular senescence using LAP and HER2+ breast cancer cells and found that reversible senescence contributed to LAP resistance in HER2+ breast cancer. Then we identified ecto-5'-nucleotidase (NT5E) as a marker of reversible senescence in HER2+ breast cancer. Based on this, we constructed NT5E targeted nanobubbles (NT5E-FITC-NBs) as a new molecular imaging modality which could both target reversible senescent cells and be used for ultrasound imaging. NT5E-FITC-NBs showed excellent physical and imaging characteristics. As an ultrasound contrast agent, NT5E-FITC-NBs could accurately identify reversible senescent cells both in vitro and in vivo. Our data demonstrate that cellular senescence-based ultrasound targeted imaging can identify reversible senescence and evaluate LAP resistance effectively in HER2+ breast cancer, which has the potential to improve cancer outcomes by altering treatment strategies ahead of aggressive recurrences. Overall design: We performed gene expression profiling analysis using data obtained from RNA-seq of three kinds of cells.These cells were SKBR3 cells(SK), senescent SKBR3 cells(SKBR3 cells were treated with 250 nM lapatinib for two weeks,referred to as SK-S or SK-la) and senescence escaped SKBR3 cells(The senescent SKBR3 cells were then cultured in the absence of lapatinib and the cells began to actively proliferate.The reproliferating cells were identified as senescence escape cells and were referred as SK-T. )