Abstract 6132: Impact of treatment with agents targeting different members of HER family, CDKs and downstream cell signaling molecules on growth and migration of stomach cancer cells
Authors: Al-Janaby Tina , Nahi Narmin , Khelwatty Said A. , Seddon Alan , Bagwan Izhar , Modjtahedi Helmout 
Published: April 2023

Abstract
Stomach cancer ranks fifth and fourth for the incidence and mortality rate for cancer worldwide, respectively. In recent years, several inhibitors with specificity to one or more members of human epidermal growth factor receptor (HER) family have been approved for the treatment of patients with different cancer types. Of these, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients and with tumor heterogeneity being one contributing factor. In this study, we investigated the effect of various types of targeted agents on the growth in vitro of a panel of human stomach cancer cells (HSCCLs) and the impact of stomach cancer proliferation rate on the anti-tumor activities of these agents. Moreover, we investigated the cell surface expression of the HER family members, other biomarkers such as C-Met, Alk-7 and cancer stem cell makers CD44 and CD133 by flow cytometry and the effect various targeted agents on tumor migration using Incucyte. Of the 18 agents examined, the CDK 1/2/5/9 inhibitor dinaciclib was the most effective and inhibited the growth of all human HSCCLs at IC50 values between 1nM to 9nM. Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual EGFR/HER2 TKI lapatinib and the EGFR specific TKI erlotinib in inhibiting the growth of HSCCLs. Interestingly, the HER-2 overexpressing cells lines NCI-N87 (Mean Fluorescence Intensity =596) was most sensitive to the HER inhibitors. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs and with the IC50 values ranging from 2nM to 7uM. Interestingly, many of these agents were more effective in inhibiting the growth of HSCCLs when proliferating at slower rate. Of the agent examined, neratinib, afatinib, dinacicilib, dasatinib, stattic and miransertib also inhibited the migration of stomach cancer cells. Finally, treatment with a combination of afatinib with dinaciclib, capmatinib, dasatinib, stattic, ponatinib or miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells. As stomach cancer cells are heterogenous in nature, our results support further research on the therapeutic potential of the CDK dinaciclib in combination with a pan-HER inhibitor in stomach cancer.
Citation Format: Tina Al-Janaby, Narmin Nahi, Said A. Khelwatty, Alan Seddon, Izhar Bagwan, Helmout Modjtahedi. Impact of treatment with agents targeting different members of HER family, CDKs and downstream cell signaling molecules on growth and migration of stomach cancer cells. [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 6132.