Abstract Background: Trastuzumab (Tmab) is an effective monoclonal antibody against advanced esophago-gastric cancers (GCs) with HER2 amplification. Unfortunately, the efficacy of Tmab is limited due to primary and acquired resistance to this agent. Q702 is a novel, orally available small molecule that selectively inhibits three receptor tyrosine kinases: Axl, Mer, and CSF1R. Here, we describe a therapeutic synergism between Tmab and Q702 in HER2+ GC cells. Material and Methods: After screening 37 GC cell lines (J-S Kim et al Int. J. Mol. Sci. 2024, 25(11), 5975), the following GC cells were evaluated: HER2 amplification -positive (HER2+) and Tmab-sensitive NCI-N87 and OE19, HER2+ Tmab-resistant OE33, ESO26, SNU-216, MKN7, YCC19, YCC33, and YCC38 and HER2 negative AGS and SNU638. We assessed the cytotoxic response of these GC cells to trastuzumab alone or in combination with Q702 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay, and clonogenic cell survival assays. Western blots were performed to assess biochemical changes, especially those related with HER2 signaling components. The statistical significance of differences of colony numbers were determined by using the Kruskal-Wallis test. Results: HER2+ Tmab-resistant GC cells showed relatively higher expression of AXL than HER2+ Tmab-sensitive GC cells. Q702 significantly decreased the number of colonies in clonogenc assays and exerted dose-dependent effects in HER2+ GC cells. Additionally, we observed that treatment with trastuzumab in combination with Q702 induced a statistically significant decrease of the colonies in HER2 + GC cells, both Tmab-sensitive and Tmab-resistant. Combination with Q702 resulted in decreased phosphorylation of HER2 and its downstream targets, AKT and ERK, in Tmab-resistant HER2+ cells. No growth inhibition was detected in HER2-GC cells treated with Tmab alone or combination. Conclusion: Collectively, these data support that Q702 could overcome primary resistance to Tmab in HER2+ GC cells. Citation Format: Mi Young Kim, Yoonji Lee, Kiyean Nam, Jin-Soo Kim. Q702 enhances trastuzumab efficacy for HER2 + gastric cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2975.
Kim et al. (Fri,) studied this question.