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

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 therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials. CDK4/6 inhibition in glioblastoma activates the c-Met and TrkA-B pathways mediated by NF-κB and can be reversed by a dual c-Met/Trk inhibitor. .

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

“…This effect was produced by abemaciclib activation of NF-κB that, in turn, induced the production of hepatocyte growth factor, brainderived neurotrophic factor, and nerve growth factor, activating c-Met and TrkA-B. Then, dual inhibition of c-Met/Trk and CDK4/6 was proposed for a clinical trial (248). In addition, prolonged exposure to pablociclib was reported to induce fibroblast senescence in an NF-κB dependent manner, and these cells were able to enhance melanoma growth in mice and recruitment of MDCS to the tumor bed.…”

Neurotrophin Signaling in Medulloblastoma

“…Conversely, knockdown or pharmacological inhibition of TrkB and TrkC decreased glioma CSC growth [63]. TrkA and TrkB can be activated in GBM cells, and combined inhibition of Trk and c-Met reduces the resistance against CDK4/6 inhibition in experimental GBM [64]. Selective TrkB inhibition effectively and dose-dependently impairs the viability of human GBM cells in vitro [65].…”

Metabolic Reprogramming by c-MET Inhibition as a Targetable Vulnerability in Glioblastoma

“…Similar to the observations in melanoma, our group made the recent and related discovery that in glioblastoma targeting MET signaling, a receptor kinase that connects to the ERK signaling pathway, elicits an increase of oxidative metabolism through activation of fatty acid oxidation (FAO) [6]. MET signaling remains a critical pathway in glioblastomas, but thus far akin to other molecular targets therapeutics targeting of MET fell rather short of expectations [7,8]. The causes are multiple and include the fact that inhibitors may not cross the blood brain barrier very well.…”