KEY TAKEAWAYS
- The study aimed to devise a precise treatment to restore temozolomide sensitivity in the mesenchymal glioblastoma.
- The results demonstrated that combining p38MAPK and MEK inhibitors extends temozolomide sensitivity, offering a potential precision therapy for mesenchymal glioblastoma.
Glioblastoma’s precision treatment focuses on molecular subtypes, focusing on the temozolomide-resistant mesenchymal subtype. Targeted therapies aim to overcome this resistance, enhancing outcomes in brain cancer management.
Hong Sheng Cheng and the team spearheaded the study that aimed to devise a tailored therapy to restore temozolomide sensitivity in the mesenchymal subtype of glioblastoma.
The study integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells’ public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays, and comet assays were employed to explore the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells.
The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was assessed utilizing an intracranial patient-derived tumor xenograft model, focusing on survival analysis.
Their transcriptomic-kinomic integrative analysis identified p38MAPK as the primary target, delineating patient subtypes and offering prognostic insights. Repurposed p38MAPK inhibitors synergized with temozolomide, enhancing intracellular retention and DNA damage. Mesenchymal cells demonstrated adaptive chemoresistance to p38MAPK inhibition via a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively preserved temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts.
The study found that the resistance to temozolomide in mesenchymal glioblastoma correlates with p38MAPK activation, while adaptive chemoresistance involves MEK/ERK signaling. Combining p38MAPK and MEK inhibitors extends temozolomide sensitivity, offering a potential precision therapy for the mesenchymal subtype.
Source: https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noae028/7609458
Cheng HS, Chong YK, Lim EKY, et al. (2024) ‘’Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.’’ Neuro-Oncology, 2024;, noae028, https://doi.org/10.1093/neuonc/noae028.
