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Stress granule assembly represents a therapeutic vulnerability in super-enhancer-driven circMLB-mediated glioblastoma
Ruixiang Huang1, Zhihao Yang2, Yongfei Dong3
1Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui Province, 230601, China; Institute of Orthopaedics, Research Center for Translational Medicine, The Second Hospital of Anhui Medical University, Anhui Medical University, Hefei, 230601, China; Department of Neurosurgery, The Second Affiliated Hospital of Anhui Medical University, 678 Fu Rong Road, Hefei, Anhui Province, 230601, China.
Abstract:
Resistance to temozolomide (TMZ) is a major driver of treatment failure and high mortality in patients with glioblastoma (GBM). However, the mechanisms underlying TMZ resistance, especially intrinsic resistance, remain incompletely elucidated. Through integrative multi-omics analyses, we identified a novel super-enhancer-driven circular RNA, circMLB, which is highly overexpressed in TMZ-R GBM. Both in vitro and in vivo studies robustly demonstrate that circMLB significantly enhances TMZ resistance in GBM. Mechanistically, the transcription factor PAF1 forms a protein complex with BRD4 that is enriched in the super-enhancer region, thereby upregulating circMLB expression. Furthermore, highly expressed circMLB directly binds to PKR, triggering stress granule assembly and ultimately reinforcing TMZ resistance in GBM. Importantly, we identified a novel PKR inhibitor, lurasidone, which synergizes with TMZ to exert potent anti-tumor activity against TMZ-R GBM in preclinical models. Our findings uncover a previously unrecognized SE-circMLB-PKR axis mediating intrinsic TMZ resistance and highlight the lurasidone-TMZ combination as a promising therapeutic strategy to surmount TMZ resistance in GBM.
Insights
A novel circular RNA, circMLB, drives glioblastoma resistance to temozolomide (TMZ). Inhibiting PKR with lurasidone synergizes with TMZ, offering a new strategy against this aggressive brain cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Temozolomide (TMZ) resistance is a critical challenge in glioblastoma (GBM) treatment, leading to poor outcomes.
- Mechanisms of intrinsic TMZ resistance in GBM are not fully understood.
- Circular RNAs are emerging as key regulators in cancer progression and drug resistance.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying intrinsic temozolomide resistance in glioblastoma.
- To identify novel therapeutic targets and strategies to overcome TMZ resistance in GBM.
Main Methods:
- Integrative multi-omics analyses to identify key molecular players.
- In vitro and in vivo experiments to validate the role of circMLB in TMZ resistance.
- Investigation of the circMLB-PKR interaction and its downstream effects.
- Preclinical testing of lurasidone in combination with TMZ.
Main Results:
- A novel super-enhancer-driven circular RNA, circMLB, was identified and found to be overexpressed in TMZ-resistant GBM.
- circMLB significantly enhances TMZ resistance in GBM through in vitro and in vivo models.
- The transcription factor PAF1 and BRD4 complex upregulates circMLB expression.
- circMLB binds to PKR, promoting stress granule assembly and reinforcing TMZ resistance.
- Lurasidone, a PKR inhibitor, synergizes with TMZ to demonstrate potent anti-tumor activity in preclinical TMZ-resistant GBM models.
Conclusions:
- A novel super-enhancer-circMLB-PKR axis is identified as a mediator of intrinsic TMZ resistance in GBM.
- Targeting this axis, specifically with the combination of lurasidone and TMZ, represents a promising therapeutic strategy for overcoming TMZ resistance in GBM.
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