Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer

Patrick N. Song, Ameer Mansur, Yun Lu, Deborah Della Manna, Andrew Burns, Sharon Samuel, Katherine Heinzman, Suzanne E. Lapi, Eddy S. Yang, Anna G. Sorace

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 languageEnglish
Article number1015
JournalCancers
Volume14
Issue number4
DOIs
StatePublished - 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

Fingerprint

Dive into the research topics of 'Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer'. Together they form a unique fingerprint.

Cite this