Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer.
Patrick N SongAmeer MansurYun LuDeborah Della MannaAndrew C BurnsSharon SamuelKatherine HeinzmanSuzanne E LapiEddy Shih-Hsin YangAnna G SoracePublished in: Cancers (2022)
DNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breast cancer. This is monitored through in vitro and in vivo studies of phosphorylated γ-H2AX, [ 18 F]-fluoromisonidazole (FMISO)-PET, and transcriptomic analysis. In vitro, HER2+ breast cancer cell lines were treated with trastuzumab prior to radiation and DNA double-strand breaks (DSB) were quantified. In vivo, HER2+ human cell line or patient-derived xenograft models were treated with trastuzumab, fractionated radiation, or a combination and monitored longitudinally with [ 18 F]-FMISO-PET. In vitro DSB analysis revealed that trastuzumab administered prior to fractionated radiation increased DSB. In vivo, trastuzumab prior to fractionated radiation significantly reduced hypoxia, as detected through decreased [ 18 F]-FMISO SUV, synergistically improving long-term tumor response. Significant changes in IL-2, IFN-gamma, and THBS-4 were observed in combination-treated tumors. Trastuzumab prior to fractionated radiation synergistically increases radiotherapy in vitro and in vivo in HER2+ breast cancer which is independent of anti-HER2 response alone. Modulation of the tumor microenvironment, through increased tumor oxygenation and decreased DNA damage response, can be translated to other cancers with first-line radiation therapy.
Keyphrases
- epidermal growth factor receptor
- radiation therapy
- radiation induced
- metastatic breast cancer
- dna damage
- endothelial cells
- dna damage response
- early stage
- computed tomography
- locally advanced
- dna repair
- tyrosine kinase
- single cell
- dendritic cells
- high glucose
- oxidative stress
- small cell lung cancer
- young adults
- positron emission tomography
- rectal cancer
- breast cancer risk
- case control
- blood flow