Abstract

HER2–targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2–targeted therapies, have demonstrated sensitivity to poly–(ADP– ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2– breast cancer cells. Further, we evaluated the utility of 3′–Deoxy–3′–[18F]–fluorothymidine positron emission tomography ([18F]FLT–PET) imaging for early response assessment in a HER2+ patient derived xenograft (PDX) model of breast cancer. In vitro , we observed decreased cell viability. In vivo, we observed decreased inhibition in tumor growth in combination therapies, compared to vehicle and monotherapy–treated cohorts. Early assessment of cellular proliferation corresponds to endpoint cell viability. Standard summary statistics of [18F]FLT uptake from PET were insensitive to early proliferative changes. Meanwhile, histogram analysis of [18F]FLT uptake indicated the potential translatability of imaging proliferation biomarkers. This study highlights the potential of combined trastuzumab and PARP inhibition in HER2+ breast cancer, while demonstrating a need for optimization of [18F]FLT–PET quantification in heterogeneous models of HER2+ breast cancer.

Document Type

Article

Publication Date

5-2023

Notes/Citation Information

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.3390/biomedicines11082090

Funding Information

This project was in part supported by ACS RSG–18–006–01–CCE, NIH NCI R01CA240589, and NIH NCI R01CA276540. The research is supported by O’Neal Comprehensive Cancer Center’s Preclinical Imaging Shared Facility P30CA013148. Research reported in this publication was sup- ported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM135028. PDX tissue was collected by Baylor College of Medicine’s Patent–Derived Xenograft core and Advanced In Vivo Models Core and was supported by CPRIT Core Facilities Support Grant RP170691.

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