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Published on: January 3, 2013
Targeting MXD1 sensitises pancreatic cancer to trametinib
Shaoping Zhang1, Shuang Deng1, Ji Liu1
1State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Background:
The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear.
Objective:
We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC.
Design:
We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism.
Results:
We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation protein 1 (MXD1), which acts as a cofactor of histone methyltransferase mixed lineage leukaemia 1 to increased H3K4 trimethylation in transposable element (TE) loci, enhancing chromatin accessibility and thus the transcription of TEs. Mechanistically, enhanced transcription of TEs produces excessive double-stranded RNAs, leading to the activation of viral mimicry response and downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 expression can recover the drug vulnerability of trametinib-resistant PDAC cells to trametinib.
Conclusions:
Our study has discovered an important mechanism for trametinib resistance and identified MXD1 as a druggable target in treatment of trametinib-resistant PDAC.
Insights
Pancreatic cancer (PDAC) resistance to trametinib is linked to a viral mimicry response. Inhibiting MXD1, a key factor in this resistance, restores sensitivity to trametinib therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to trametinib therapy, limiting its clinical application.
- The molecular mechanisms driving trametinib resistance in PDAC are not well understood.
- Identifying these mechanisms is crucial for improving treatment outcomes.
Purpose of the Study:
- To elucidate the mechanisms of trametinib resistance in PDAC.
- To identify druggable targets associated with trametinib resistance.
- To enhance the efficacy of trametinib treatment for resistant PDAC.
Main Methods:
- Established patient-derived xenograft (PDX) models and primary cell lines for functional studies.
- Utilized single-cell RNA sequencing, ATAC-seq, and CUT&Tag sequencing to investigate molecular mechanisms.
- Analyzed gene expression, chromatin accessibility, and epigenetic modifications.
Main Results:
- Identified a PDAC subpopulation with hyperactivated viral mimicry response in trametinib-resistant models.
- Trametinib treatment induced MAX dimerisation protein 1 (MXD1) expression, increasing H3K4 trimethylation at transposable element (TE) loci.
- Enhanced TE transcription produced double-stranded RNAs, activating viral mimicry and oncogenic interferon-stimulated genes.
Conclusions:
- Discovered a novel mechanism of trametinib resistance in PDAC involving MXD1 and viral mimicry.
- Identified MXD1 as a potential druggable target for overcoming trametinib resistance.
- Inhibiting MXD1 expression can re-sensitize resistant PDAC cells to trametinib.
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