Pharmacodynamic Modeling Identifies Synergistic Interaction Between Chloroquine and Trastuzumab in Refractory HER2- positive Breast Cancer Cells

BACKGROUND/AIM: Despite improvements in HER2-positive breast cancer (BC) patients' outcomes with trastuzumab, the occurrence of intrinsic or acquired resistance presents a clinical challenge. Here, we quantitatively assess the combinatorial effects of chloroquine, an autophagy inhibitor, with trastuzumab on JIMT-1 cells, a HER2-positive BC cell-line primarily resistant to trastuzumab. MATERIALS AND METHODS: The temporal changes in JIMT-1 cellular viability were assessed using the CCK-8 kit, where JIMT-1 cells were exposed for 72-h to trastuzumab (0.007-17.19 μM) or chloroquine (5-50 μM) as single-agents, in combination (trastuzumab: 0.007-0.688 μM; chloroquine: 5-15 μM), or control (no drug). Concentration-response relationships were built for each treatment arm to determine drugs' concentrations inducing 50% of cell-killing (IC50). Cellular pharmacodynamic models were built to characterize the time-trajectory of JIMT-1 cellular viability under each treatment arm. The nature of trastuzumab and chloroquine interaction was quantified by estimating the interaction parameter (Ψ). RESULTS: ), validating chloroquine's superior anti-cancer effect on JIMT-1 cells compared to trastuzumab. The time-delay for chloroquine cell-killing was twice longer than that for trastuzumab (17.7 vs. 7 h), suggesting a chloroquine time-dependent anti-cancer effect. The Ψ was determined at 0.529 (Ψ<1), indicating a synergistic interaction. CONCLUSION: This proof-of-concept study on JIMT-1 cells identified chloroquine and trastuzumab synergistic interaction, warranting further in vivo investigations.