Abstract 595: Targeting metabolic vulnerability in brain-metastatic HER2+ breast cancer

Abstract

Abstract Introduction: Human epidermal growth factor receptor 2 positive (HER2+) breast cancer tumors have increased risk of brain metastases at an advanced stage. The brain’s microenvironment is relatively low in lipids; therefore, breast cancer cells that colonize the brain have an increased expression of fatty acid synthesis enzymes. This presents a potential vulnerability that could be targeted. There is an established feed-forward relationship between HER2 and fatty acid synthase (FASN) where HER2 signaling activates FASN signaling. FASN inhibition has been shown to decrease cell invasion in a preclinical breast cancer model. We hypothesize that targeting HER2+ breast cancer cells with a HER2 tyrosine kinase inhibitor (TKI) or HER2 antibody-drug conjugate (ADC) in combination with a FASN inhibitor will lead to synergistic cell death. We also hypothesize that FASN inhibitors alone impede outgrowth and invasion of HER2+ breast cancer cells. Methods: We performed combinatorial drug-screening using the Chou-Talalay method in vitro using HER2+ breast cancer cell spheroids and tested the impact of FASN inhibitors alone on the outgrowth of these spheroids embedded in Matrigel. The HER2+ cell lines we used include JIMT-1, JIMT-1-BR3, SUM190, and SUM-190-BR3. JIMT-1-BR3 and SUM190-BR3 are brain-seeking subclones of the primary cell lines generated by serial passaging through mice with collection of cells in the brain. In combinatorial drug-screening, we calculated combination index (CI) values for the combination of each of two FASN inhibitors (TVB-2640 and BI-99179) with each of three clinically approved HER2 TKIs (Tucatinib, Lapatinib, and Neratinib) and each of two ADCs (Trastuzumab deruxtecan and Trastuzumab emtansine). The experiments were performed in both media supplied with fetal bovine serum (FBS) and with lipid-stripped FBS, to mimic the brain microenvironment. Results: Drug screening revealed that FASN inhibitors are toxic only at high doses in cell viability assays. However, we calculated combination index (CI) values using the Chou-Talalay method indicative of synergy for the combinations of the FASN inhibitors with the HER2-targeting drugs. Moreover, we discovered that the FASN inhibitors TVB-2640 and BI-99179 alone significantly impede the outgrowth of the spheroids embedded in Matrigel. Conclusions: Based on these promising preliminary data, we will evaluate these results in vivo. Breast cancer patients harboring brain metastases are difficult to treat, and they suffer from severe symptoms impacting daily life and have poor survival rates. Our ultimate goal is to launch a clinical trial to test one or more of these drug combinations to provide an additional therapeutic option that may improve patients’ lives and decrease mortality. Citation Format: Habib Serhan, Liwei Bao, Xu Cheng, Sofia Merajver, Aki Morikawa, Nathan Merrill. Targeting metabolic vulnerability in brain-metastatic HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 595.