Introduction: Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. In colon cancer, knockdown of ID1 and ID3 have been shown to impair self-renewal of colon cancer tumor initiating cells, reduce tumor growth and enhance sensitivity to chemotherapy. In this study, we investigated the role of ID1 in tumor initiation, treatment resistance, and disease recurrence in glioblastoma.
Methods: To elucidate the oncogenic properties of ID1, we used the CRISPR-Cas9 mediated lentiviral system to knockout ID1 in glioblastoma (U251), breast adenocarcinoma (MDA-MB-231), and melanoma (A375) cells. In vtiro proliferation assays were performed, as were assays to determine temozolomide sensitivity. Xeongraft studies utilizing luciferase-expressing glioma cells and bioluminescence were performed to study tumorigenic potential and tumor progression in vivo. The neuroleptic drug pimozide was identified as a potent chemical inhibitor of ID1.
Results: We show that ID1 is necessary for tumor initiation and tumor growth in multiple solid cancers, including glioblastoma, breast adenocarcinoma and melanoma. Through induction of EGF, ID1 maintains EGFR in a continuously activated state. ID1-dependent EGFR activation renders cancer cells resistant to chemotherapy; inhibition of ID1 by genetic knockout or with the antipsychotic agent, pimozide, enhances the cytotoxic effect of the alkylating agent, temozolomide.
Conclusions: Taken together, our data suggests that ID1 regulates multiple tumor-promoting pathways in cancer by positively regulating EGF expression and thereby EGFR activity. Targeting ID1 and thereby the EGFR pathway with drugs such as pimozide may represent a novel and promising strategy for therapy in patients with glioblastoma.
Patient Care: We have identified an FDA-approved drug that crosses the blood-brain barrier (pimozide) and enhances the cytotoxic effect of temozolomide on glioma cells. We are performed preclinical studies to determine if this finding merits translation to patients.
Learning Objectives: - to describe the role of ID1 in glioblastoma initiation
- to understand the mechanism underlying ID1-mediated treatment resistance in glioblastoma
- to understand the role of ID1 inhibition in glioblastoma treatment