Abstract 6133: Growth response and migration of brain cancer cell lines to treatment with agents targeting different members of the HER family, CDKs and other signalling pathways
Authors: Mulliqi Ermira , Khelwatty Said A. , Morgan Anna L. , Ashkan Keyoumars , Modjtahedi Helmout 
Published: April 2023

Glioblastoma (GB) is one of the most frequent primary brain tumors in adults with an extremely poor prognosis and a very high demand for novel therapies. Poor prognosis has been linked to its complex biology, tumor heterogeneity and an increased activation of signaling pathways through various growth factor receptors signaling pathway. In particular, aberrant expression and activation of epidermal growth factor receptor (EGFR) expression has been found to be common in patients with GBM. However, no EGFR inhibitor has yet been approved for the treatment of patients with brain tumor and there is currently no comprehensive study of all members of the HER family in the progression brain tumors. The aim of this study was to investigate the role of all members of the HER family (EGFR, HER2 HER3 and HER4), other growth factor receptors (e.g., C-MET) and downstream cell signaling pathways in the growth of a panel of human brain cancer cell lines (HBCCLs) and response to therapeutic interventions. Using Sulforhodamine B colorimetric assay, the growth response of four HBCCLs to treatment with 18 agents targeting different members of the HER family and other growth receptors (e.g. C-met/ALK 7, PDGFRs, FGFRs, C-kit), cyclin dependent kinases inhibitors (e.g. CDKs 1/2/5/9, CDK4/6) and downstream signaling molecules (e.g. STAT3, Src, Abl) was examined. We determined the expression level of all members of the HER family in brain cancer cells by flow cytometry and Western blot and the effect of these agents on migration of brain cancer cells were determined using Incucyte. Of the targeted agents examined, the CDK 1/2/5/9 inhibitor dinaciclib was the most potent and inhibited growth for all four HBCCLs with an IC50 below 10nM. Of the HER inhibitors, neratinib and afatinib were more effective than erlotinib and lapatinib and inhibiting the growth of all HBCCLs at IC50 values below 700nM and 1.9 µM, respectively. Treatment with Src/Abl/c-kit inhibitor dasatinib, STAT3 inhibitor static, Abl/PDGFRα/VEGFR2/FGFR1 inhibitor Ponatinib and the TRK/ROS/ALK inhibitor entrecitinb also inhibited the growth of HBCCLs with IC50 value ranging from 0.06 - 2.96 µM, 1 - 3.8µM, 0.19- 0.42 μM and 2.85- 3.47μM, respectively. Interestingly, these agents were more effective in inhibiting growth of HBCCLs when proliferating at a slower rate. In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib, dasatanib, static and trametinib inhibited the migration of brain tumor cells. Finally, treatment with neratinib in combination with Palbociclib, AZD4547, trametinib and miransertib inhibited the growth of HBCCLs synergistically. Taken together, our results support further investigation on the therapeutic potential of irreversible pan HER in combination with the CDK inhibitor dinaciclib and other targeted agents in brain cancer.

Citation Format: Ermira Mulliqi, Said A. Khelwatty, Anna L. Morgan, Keyoumars Ashkan, Helmout Modjtahedi. Growth response and migration of brain cancer cell lines to treatment with agents targeting different members of the HER family, CDKs and other signalling pathways. [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 6133.