Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide

Hong Sheng Cheng; Yuk Kien Chong; Eldeen Kai Yi Lim; Xin Yi Lee; Qing You Pang; Wisna Novera; Charlie Marvalim; Jeannie Xue Ting Lee; Beng Ti Ang; Carol Tang; Nguan Soon Tan

doi:10.1093/neuonc/noae028

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide

Neuro Oncol. 2024 Feb 16:noae028. doi: 10.1093/neuonc/noae028. Online ahead of print.

Authors

Hong Sheng Cheng^{1

2}, Yuk Kien Chong³, Eldeen Kai Yi Lim², Xin Yi Lee², Qing You Pang³, Wisna Novera³, Charlie Marvalim², Jeannie Xue Ting Lee¹, Beng Ti Ang^{4

5}, Carol Tang^{3

5}, Nguan Soon Tan^{1

2}

Affiliations

¹ Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
² School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore.
³ Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore 308433, Singapore.
⁴ Department of Neurosurgery, National Neuroscience Institute, Singapore 308433, Singapore.
⁵ Duke-National University of Singapore Medical School, Singapore 169857, Singapore.

PMID: 38366847
DOI: 10.1093/neuonc/noae028

Abstract

Background: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype.

Methods: We 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 used to examine 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 evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis.

Results: Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favourably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintains temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts.

Conclusion: Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.

Keywords: MAPK signaling; Precision medicine; brain cancer; glioma; targeted therapy.