Abnormal alternative splicing promotes tumor resistance in targeted therapy and immunotherapy

Deng, Kun; Jian, Yao; Huang, Jialu; Ding, Yubo; Zuo, Jianhong

doi:10.1016/j.tranon.2021.101077

Cited by 21 publications

(13 citation statements)

References 95 publications

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“…As a result of this, the CD19 antigen is unable to properly adhere to the cell surface [ 155 ]. Deng et al showed that malignant B cells that express CD19 transcripts without exon 2 had reduced SRS3 gene expression [ 156 ]. The SRS3 gene (locus 6p21.31-p21.2) encodes a splicing factor that affects pre-mRNA processing and is involved in the recognition of terminal exons [ 157 , 158 ].…”

Section: Resultsmentioning

confidence: 99%

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

Jędraszek

Malczewska

Parysek-Wójcik

et al. 2022

IJMS

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Despite the rapid development of medicine, even nowadays, acute lymphoblastic leukemia (ALL) is still a problem for pediatric clinicians. Modern medicine has reached a limit of curability even though the recovery rate exceeds 90%. Relapse occurs in around 20% of treated patients and, regrettably, 10% of diagnosed ALL patients are still incurable. In this article, we would like to focus on the treatment resistance and disease relapse of patients with B-cell leukemia in the context of prognostic factors of ALL. We demonstrate the mechanisms of the resistance to steroid therapy and Tyrosine Kinase Inhibitors and assess the impact of genetic factors on the treatment resistance, especially TCF3::HLF translocation. We compare therapeutic protocols and decipher how cancer cells become resistant to innovative treatments—including CAR-T-cell therapies and monoclonal antibodies. The comparisons made in our article help to bring closer the main factors of resistance in hematologic malignancies in the context of ALL.

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Section: Resultsmentioning

confidence: 99%

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

Jędraszek

Malczewska

Parysek-Wójcik

et al. 2022

IJMS

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“…Among proteins with an important role in the alternative splicing processes, we can highlight the significantly upregulated SNRPB2, SNRNP70 and SNRPA1 proteins [ 90 ] (GO Biological Process, FDR < 0.05) ( Figure S4 ) ( Figure 6 2D). Studies have confirmed that the abnormal expression of the splicing proteins can lead to inappropriate splicing mechanisms, causing tumor progression [ 91 ]. Denga et al also suggested that these disordered splicing mechanisms could promote the loss of cell surface antigens, which are crucial in melanoma and immune cell fusion that might contribute to immunotherapy resistance [ 91 ].…”

Section: Resultsmentioning

confidence: 99%

“…Studies have confirmed that the abnormal expression of the splicing proteins can lead to inappropriate splicing mechanisms, causing tumor progression [ 91 ]. Denga et al also suggested that these disordered splicing mechanisms could promote the loss of cell surface antigens, which are crucial in melanoma and immune cell fusion that might contribute to immunotherapy resistance [ 91 ]. In the clinical field, the anti-spliceosome therapies are currently debated in their application of spliceosome machinery targeting [ 92 ].…”

Section: Resultsmentioning

confidence: 99%

Deep Proteomic Analysis on Biobanked Paraffine-Archived Melanoma with Prognostic/Predictive Biomarker Read-Out

Szadai

Velásquez

Szeitz

et al. 2021

Cancers

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The discovery of novel protein biomarkers in melanoma is crucial. Our introduction of formalin-fixed paraffin-embedded (FFPE) tumor protocol provides new opportunities to understand the progression of melanoma and open the possibility to screen thousands of FFPE samples deposited in tumor biobanks and available at hospital pathology departments. In our retrospective biobank pilot study, 90 FFPE samples from 77 patients were processed. Protein quantitation was performed by high-resolution mass spectrometry and validated by histopathologic analysis. The global protein expression formed six sample clusters. Proteins such as TRAF6 and ARMC10 were upregulated in clusters with enrichment for shorter survival, and proteins such as AIFI1 were upregulated in clusters with enrichment for longer survival. The cohort’s heterogeneity was addressed by comparing primary and metastasis samples, as well comparing clinical stages. Within immunotherapy and targeted therapy subgroups, the upregulation of the VEGFA-VEGFR2 pathway, RNA splicing, increased activity of immune cells, extracellular matrix, and metabolic pathways were positively associated with patient outcome. To summarize, we were able to (i) link global protein expression profiles to survival, and they proved to be an independent prognostic indicator, as well as (ii) identify proteins that are potential predictors of a patient’s response to immunotherapy and targeted therapy, suggesting new opportunities for precision medicine developments.

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“…Taken together, these samples of explanation give us insights into how alternative splicing is altered at different levels in cancers. Adding to the complexity, this mechanism has also been described as implicated in various chemoresistance mechanisms ( 87 – 89 ) (not detailed here). Therefore, RNA splicing modulation is, without a doubt, a crucial element to consider in the development of new therapeutic strategies to prevent, ameliorate treatment efficiency, and fight cancer.…”

Section: Rna Splicing and Cancermentioning

confidence: 98%

Alternative RNA splicing in cancer: what about adult T-cell leukemia?

2022

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Eukaryotic cells employ a broad range of mechanisms to regulate gene expression. Among others, mRNA alternative splicing is a key process. It consists of introns removal from an immature mRNA (pre-mRNA) via a transesterification reaction to create a mature mRNA molecule. Large-scale genomic studies have shown that in the human genome, almost 95% of protein-encoding genes go through alternative splicing and produce transcripts with different exons combinations (and sometimes retained introns), thus increasing the proteome diversity. Considering the importance of RNA regulation in cellular proliferation, survival, and differentiation, alterations in the alternative splicing pathway have been linked to several human cancers, including adult T-cell leukemia/lymphoma (ATL). ATL is an aggressive and fatal malignancy caused by the Human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes for two oncoproteins: Tax and HBZ, both playing significant roles in the transformation of infected cells and ATL onset. Here, we review current knowledge on alternative splicing and its link to cancers and reflect on how dysregulation of this pathway could participate in HTLV-1-induced cellular transformation and adult T-cell leukemia/lymphoma development.

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Abnormal alternative splicing promotes tumor resistance in targeted therapy and immunotherapy

Cited by 21 publications

References 95 publications

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia

Deep Proteomic Analysis on Biobanked Paraffine-Archived Melanoma with Prognostic/Predictive Biomarker Read-Out

Alternative RNA splicing in cancer: what about adult T-cell leukemia?

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