ADPB Sensitivity in Breast Cancer is Correlated with LAT1 Expression: An in vitro Study of a Novel Theranostic Candidate

Kharisma Perdani Kusumahstuti,1– 3,* Holis Abdul Holik,4,* Muhammad Hasan Bashari,5,* Arifudin Achmad,2,3,* Shaharum Shamsuddin,6,* Achmad Hussein Sundawa Kartamihardja2,3,* 1Doctoral Study Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, Jawa Barat, Indonesia; 2Department of Nuclear Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Jawa Barat, Indonesia; 3Department of Nuclear Medicine and Theranostic Molekuler, Hasan Sadikin Hospital, Bandung, Jawa Barat, Indonesia; 4Department of Pharmaceutical Analysis & Medicinal Chemistry, Faculty of Pharmacy Universitas Padjadjaran, Bandung, Jawa Barat, Indonesia; 5Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Jawa Barat, Indonesia; 6School of Health Sciences, Universiti Sains Malaysia, Kota Bharu, KTN, Malaysia*These authors contributed equally to this workCorrespondence: Kharisma Perdani Kusumahstuti, Doctoral Study Program, Faculty of Medicine, Universitas Padjadjaran, Bandung, Jawa Barat, 40125, Indonesia, Email [email protected]: The most common cancer in women worldwide is breast cancer. Current systemic chemotherapies do not target specific cells, which makes them toxic to normal cells. The L-type amino acid transporter 1 (LAT1) is overexpressed in a lot of cancers, also in breast cancer. Few ligand such as JPH203 (KYT-0353), a known tyrosine analogue that specifically blocks LAT1, but have limitation. It has led to efforts to create next-generation LAT1 inhibitors or prodrugs with better qualities for target therapy or diagnostic.Purpose: We investigated a new agent (S)-2-amino-4-(3,5-dichlorophenyl) butanoic acid (ADPB) as a new LAT1 inhibitor in three breast cancer cell lines: MCF-7 luminal A, HCC1954 HER2+, and MDA-MB-231 triple-negative. We hypothesized that the levels of LAT1 expression would influence the efficacy of ADPB. This could lead to a treatment that is more targeted and less harmful.Methods: We used RT-qPCR to determine the LAT1 mRNA expression in each cell line and MTT for find IC50 values. These cells were given ADPB (0– 160 μM) for 72 hours. There were three replication tests.Results: ADPB diminished the viability of cells in all cell lines, and the effect was dose-dependent. MDA-MB-231 was the most sensitive cell line (IC50 = 118,1 μM 95% Cl (118,25– 118,48), HCC-1954 was the middle-sensitive cell line (IC50 = 126,2 μM 95% Cl (126,11– 126,68), and MCF-7 was the least sensitive cell line (IC50 = 127,3 μM 95% Cl (127,9– 131,23). Study found an inverse relationship between LAT1 expression and IC50 in all cell lines, with higher LAT1 levels correlated with lower IC50.Conclusion: In this exploratory in vitro study, ADPB predominantly induces cytostatic effects, with cellular sensitivity associated with LAT1 expression in breast cancer cell line.Keywords: LAT1, amino acid transporter, breast cancer, targeted therapy, cytostatic, theranostic agent