Abstract
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.
Original language | English |
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Article number | 1015 |
Journal | Cancers |
Volume | 14 |
Issue number | 4 |
DOIs | |
State | Published - Feb 1 2022 |
Bibliographical note
Funding Information:This study was supported by the American Cancer Society (RSG-18-006-01-CCE, 2019-2021) and National Cancer Institute (R01CA240589) to AGS. The authors would like to thank the UAB Comprehensive Cancer Center’s Preclinical Imaging Shared Facility (P30CA013148).
Funding Information:
Funding: This study was supported by the American Cancer Society (RSG-18-006-01-CCE, 2019-2021) and National Cancer Institute (R01CA240589) to AGS. The authors would like to thank the UAB Comprehensive Cancer Center’s Preclinical Imaging Shared Facility (P30CA013148).
Funding Information:
Acknowledgments: Flow cytometry analysis and experiments were conducted at the UAB Comprehensive Flow Cytometry Core (P30 AR048311 and P30 AI027667). PDX tissue was collected by Baylor College of Medicine’s Patient-Derived Xenograft and Advanced In Vivo Models Core and was supported by CPRIT Core Facilities Support Grant RP170691 and P30 Cancer Center Support Grant NCI-CA125123.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- BCM 3472
- BT474
- MDA-MB-361
- PDX
- PET
- Synergy
- Trastuzumab
- [ F]-FMISO
ASJC Scopus subject areas
- Oncology
- Cancer Research