Combined c-Met/Trk Inhibition Overcomes Resistance to CDK4/6 Inhibitors in Glioblastoma

Cancer Research
Inan OlmezBenjamin Purow

Abstract

Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB-mediated upregulation of hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeu...Continue Reading

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Citations

Dec 22, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hehua XiongPengwu Zheng
Apr 8, 2020·Oncoscience·Trang Thi Thu NguyenMarkus D Siegelin
Oct 9, 2019·Cell Cycle·Hanchen LiWalimuni Sandaroo Mendis Abeysekara Wijayakulathilaka
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Jan 27, 2021·Critical Reviews in Oncology/hematology·Fatemeh MoosaviOmidreza Firuzi

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