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. 2025 Jan 23;17(3):375.
doi: 10.3390/cancers17030375.

Multikinase Treatment of Glioblastoma: Evaluating the Rationale for Regorafenib

Ana Maria Muñoz-Mármol  1 , Bárbara Meléndez  2 , Ainhoa Hernandez  3   4   5 , Carolina Sanz  1 , Marta Domenech  3   4   5 , Oriol Arpí-Llucia  6 , Marta Gut  7 , Anna Esteve  3   4   5 , Anna Esteve-Codina  7 , Genis Parra  7 , Cristina Carrato  1 , Iban Aldecoa  8 , Mar Mallo  9 , Estela Pineda  10 , Francesc Alameda  11 , Nuria de la Iglesia  12 , Eva Martinez-Balibrea  5   13 , Anna Martinez-Cardús  4   5 , Anna Estival-Gonzalez  14 , Carmen Balana  4
Affiliations

Multikinase Treatment of Glioblastoma: Evaluating the Rationale for Regorafenib

Ana Maria Muñoz-Mármol et al. Cancers (Basel). .

Abstract

We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib's binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs > 5, and/or gene overexpression. Regorafenib did not target all 46 PKs. For the 46-gene set, 40 genes (86.9%) and 73 patients (70.8%) harbored at least one alteration in genes encoding targetable PKs, but putative oncogenic alterations were present in only 34 patients (33%). In the 18-gene set, 18 genes (100%) and 48 patients (46.6%) harbored alterations, but putative oncogenic alterations were detected in only 26 patients (25.2%). Thirty patients (29.1%) had oncogenic alterations in the 18-gene set and/or in angiogenesis-related genes. Around 33% of patients had oncogenic alterations in any of the 46 potential targets. Additionally, the suboptimal dosing of regorafenib, due to its poor penetration of the blood-brain barrier, may reduce the likelihood of effectively targeting certain PKs. Future use of multi-target drugs must be guided by a thorough understanding of target presence, effective inhibition, and the drug's ability to reach brain tumors at adequate concentrations.

Keywords: glioblastoma; molecular target; multikinase treatment; regorafenib.

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Conflict of interest statement

The authors declare no potential conflicts of interest for the data they are presenting. However, individual disclosures are as follows: Estela Pineda served in a consultant advisory role for Servier, Novocure, Global CNS Council, and GlaxoSmithKline and participated in the speakers’ bureau for Novocure. Marta Domenech was part of the speakers’ bureau for Bristol-Myers Squibb and Roche, received meeting assistance support from Lilly and Takeda, and has received a research project grant from Roche. Ainhoa Hernandez participated in the speakers’ bureau for Roche and received meeting assistance support from Roche, Sanofi, and Merck Sharp and Dohme. Carmen Balana served in an advisory role for MEDAC and received speakers’ bureau and meeting assistance support from Servier.

Figures

Figure 1
Figure 1
Molecular alterations found in our series of patients for the 46 genes encoding PKs potentially targetable by regorafenib.
Figure 2
Figure 2
Molecular alterations detected in the 46 genes included in our study compared with the minimal regorafenib concentration (in nM) necessary for inhibition or affinity. Data for KD and IC50 have been merged to simplify the figure. Columns show the number of alterations detected in each gene (left y axis). Dots show KD/IC50 in nM (right y axis). Green columns indicate genes involved in angiogenesis pathways. Dashed line represents the limit of ≤100 to determine a potential positive target affinity or inhibition.
Figure 3
Figure 3
Study design and summary of results. We analyzed WES and RNA-seq data for tumor samples from 103 glioblastoma patients. We assessed mutations, amplifications, copy number variants (CNV) (as a surrogate for gene amplification), and expression in 46 genes encoding protein kinases (PKs) potentially inhibited by regorafenib. We then focused on 18 genes encoding PKs inhibited by regorafenib at clinically achievable concentrations. In addition, we performed a functional enrichment analysis of the 46 genes and found that 19 are involved in angiogenesis, 5 of which are not included in the 18-gene set. Putative oncogenic alterations comprised oncogenic/likely oncogenic mutations, gene amplification, and/or gene overexpression. Data in patients are shown for the 46-gene set, the 18-gene set, and a 23-gene set (comprising the 18 genes plus the 5 additional genes involved in angiogenesis). Results were calculated based on the presence of any alterations excluding benign or likely benign mutations) and on only putative oncogenic alterations.
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