Quantification of the growth suppression of HER2+ breast cancer colonies under the effect of trastuzumab and PD-1/PD-L1 inhibitor

Regina Padmanabhan; Hadeel Kheraldine; Ishita Gupta; Nader Meskin; Anas Hamad; Semir Vranic; Ala-Eddin Al Moustafa

doi:10.3389/fonc.2022.977664

Quantification of the growth suppression of HER2+ breast cancer colonies under the effect of trastuzumab and PD-1/PD-L1 inhibitor

Front Oncol. 2022 Dec 7:12:977664. doi: 10.3389/fonc.2022.977664. eCollection 2022.

Authors

Regina Padmanabhan¹, Hadeel Kheraldine^{2

3}, Ishita Gupta^{2

3}, Nader Meskin¹, Anas Hamad⁴, Semir Vranic², Ala-Eddin Al Moustafa^{2

3}

Affiliations

¹ Department of Electrical Engineering, Qatar University, Doha, Qatar.
² College of Medicine, Qatar University (QU) Health, Qatar University, Doha, Qatar.
³ Biomedical Research Centre, Qatar University, Doha, Qatar.
⁴ Pharmaceutical Department at Hamad Medical Corporation, Hamad Medical Corporation, Doha, Qatar.

Abstract

Introduction: Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered.

Methods: In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents.

Results and discussion: Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell's invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Keywords: HER2; HER2/PD-1 interaction; PD-1/PD-L1; breast cancer; mathematical model.