Background: Gastric cancer is one of the most prevalent cancers in the East Asia population. The five-year survival rate is approximately 20% globally. The analysis of gene expression data suggests that anti-apoptotic protein BCL-xL may be the oncogenic driver in gastric cancer as its expression levels are much higher than BCL-2 (Pan Cancer Atlas). In this study, we investigated if a clinical stage BCL-2/BCL-xL dual inhibitor APG-1252 would elicit therapeutic activity and associated mechanisms using a panel of gastric cancer patient-derived xenograft (PDX) models. Additionally, we explored if the combination with HER2 inhibition could enhance the antitumor activity in HER2+ gastric cancer models.

Methods and Experiments: Eighteen PDX models of gastric cancer that bore high levels of BCL-xL expression (BCL-xLhigh) based on the gene expression profiles were selected for a mouse trial (n=2) with a dosage regimen of APG-1252 (100 mg/kg, BIW, IV) for three weeks. In a combination study (n=5), APG-1252 (50 mg/kg, BIW, IV) and lapatinib (100 mg/kg, QD, PO) were concurrently administered for three weeks. An advanced ELISA (MSD) and Western blot analysis were performed to detect BCL-xL complex and the protein level, respectively, in tumor samples.

Results: APG-1252 treatment resulted in tumor growth inhibition (TGI greater than 50%) in four PDXs (20%), including three exhibiting TGI greater than 80%. PD study confirmed that BCL-xL protein levels were high, and bound with pro-apoptotic proteins PUMA (major binding partner) and BIM in the xenograft tumors of these models. Generally, in comparison with hematologic cancer cells which exhibit dominant BCL-2 complexes (i.e., Toledo), the levels of BCL-xL complexes were consistently higher than those of BCL-2 complexes in the gastric cancer PDXs, implicating a crucial role of BCL-xL in the solid tumors. After treatment with APG-1252, BCL-xL:PUMA, were disrupted and, interestingly, such a decrease in BCL-xL complex signal correlated with TGI. Additionally, the baseline levels of BCL-xL complexes also correlated with TGI. Furthermore, a consequent increase in MCL-1 complexes after APG-1252 treatment indicated that such a compensatory mechanism among anti-apoptotic proteins may confer the drug resistance. Finally, in mouse tumor models derived from HER2+ gastric cancer cell line NCI-N87 or patient-derived xenografts (PDXs), combined treatment with AGP-1252 and HER2 inhibitor lapatinib synergistically inhibited tumor growth, suggesting that lapatinib may be able to increase mitochondrial priming, thus sensitizing cancer cells to APG-1252.

Conclusion: Our results demonstrate the on-target antitumor activity of APG-1252, the potential of BCL-xLhigh as a predictive biomarker, and the resistance mechanism conferred by MCL-1. Furthermore, the data provide a scientific rationale for the combined therapy with BCL-xL and HER2 inhibitors to achieve better clinical outcomes in a subset of HER2+ gastric cancers.

Citation Format: Jing Deng, Xiaojing Huang, Guoqin Zhai, Kaixiang Zhang, Jiaxing Gu, Tingting Mao, Yan Yin, Ran Tao, Douglas D. Fang, Dajun Yang, Yifan Zhai. Co-targeting BCL-xL and HER2 high expression to overcome apoptosis blockade in gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 74.