FBXW7 attenuates tumor drug resistance and enhances the efficacy of immunotherapy

Chen, Shimin; Jiang, Lin; Zhao, Jiaojiao; Qi, Lin; Liu, Jia; Wang, Qiang; Mui, Ryan; Ma, Leina

doi:10.3389/fonc.2023.1147239

Cited by 5 publications

(8 citation statements)

References 121 publications

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“…Furthermore, the 5 UTRopensea region of the FBXW7 gene was markedly less methylated in BTZ-treated MM cells. This gene and, more specifically, its downregulation have also been shown to play a role in mediating drug resistance and chemotherapy response in cancers [49][50][51][52]. After the third passage, we once again identified hypomethylation of the ORAI3 gene in MM cells incubated with BTZ and a methylation inhibitor (BTZ-sensitive cells) and hypermethylation in BTZ-resistant MM cells.…”

Section: Discussionmentioning

confidence: 70%

5-Aza-2′-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential

Łuczkowska,

Kulig,

Rusińska

et al. 2023

IJMS

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Multiple myeloma (MM) is a plasma cell malignancy that accounts for 1% of all cancers and is the second-most-common hematological neoplasm. Bortezomib (BTZ) is a proteasome inhibitor widely implemented in the treatment of MM alone or in combination with other agents. The development of resistance to chemotherapy is one of the greatest challenges of modern oncology. Therefore, it is crucial to discover and implement new adjuvant therapies that can bypass therapeutic resistance. In this paper, we investigated the in vitro effect of methylation inhibitor 5-Aza-2′-deoxycytidine on the proliferative potential of MM cells and the development of resistance to BTZ. We demonstrate that alterations in the DNA methylation profile are associated with BTZ resistance. Moreover, the addition of methylation inhibitor 5-Aza-2′-deoxycytidine to BTZ-resistant MM cells led to a reduction in the proliferation of the BTZ-resistant phenotype, resulting in the restoration of sensitivity to BTZ. However, further in vitro and ex vivo studies are required before adjuvant therapy can be incorporated into existing treatment regimens.

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Section: Discussionmentioning

confidence: 70%

5-Aza-2′-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential

Łuczkowska,

Kulig,

Rusińska

et al. 2023

IJMS

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“…Noteworthy, the growing evidence of the therapeutic approaches is proposed in terms of the treatment for MYCN-associated tumors, which targets MYCN transcription, stability, MYCN cofactors/ coregulators and MYCN downstream targets (121). In addition, the investigations targeting hedgehog signaling, cyclin D, and FBXW7 are also under development (122)(123)(124)(125). Though its relative difficulty for application to developmental disease due to the more intricate adjustment during development, not only quantitatively but also geographically, this oncologic knowledge might contribute to the development of therapeutic approaches even to the developmental disorders discussed in this review.…”

Section: Discussionmentioning

confidence: 99%

MYCN in human development and diseases

Nishio,

Kato,

Oishi

et al. 2024

Front. Oncol.

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Somatic mutations in MYCN have been identified across various tumors, playing pivotal roles in tumorigenesis, tumor progression, and unfavorable prognoses. Despite its established notoriety as an oncogenic driver, there is a growing interest in exploring the involvement of MYCN in human development. While MYCN variants have traditionally been associated with Feingold syndrome type 1, recent discoveries highlight gain-of-function variants, specifically p.(Thr58Met) and p.(Pro60Leu), as the cause for megalencephaly-polydactyly syndrome. The elucidation of cellular and murine analytical data from both loss-of-function (Feingold syndrome model) and gain-of-function models (megalencephaly-polydactyly syndrome model) is significantly contributing to a comprehensive understanding of the physiological role of MYCN in human development and pathogenesis. This review discusses the MYCN’s functional implications for human development by reviewing the clinical characteristics of these distinct syndromes, Feingold syndrome, and megalencephaly-polydactyly syndrome, providing valuable insights into the understanding of pathophysiological backgrounds of other syndromes associated with the MYCN pathway and the overall comprehension of MYCN’s role in human development.

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“…The somatic inactivating alterations were identified in three genes, namely, the CDKN2B (cyclin-dependent kinase (CDK) inhibitor 2B), the FBXW7 (F-box and WD repeat domain containing 7), and the MLH1 (MutL Homolog 1) ( Table 1 ). The first two genes are known as tumor suppression genes which are currently un-targetable, and there is evidence of their association with poor immunotherapy outcomes ( 6 , 7 ). The MLH1 gene is a member of the mismatch repair (MMR) system.…”

Section: Case 1 Presentationmentioning

confidence: 99%

Case report: Immunotherapy guided by molecular profiling of tumors: illustrative cases and literature review

Ozdogan,

Papadopoulou,

Metaxa-Mariatou

et al. 2024

Front. Med.

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Predictive biomarkers are necessary for the identification of immunotherapy-responsive patients. Tumor mutation burden (TMB), as determined by next-generation sequencing (NGS), and PD-L1 expression, as evaluated by Immunohistochemistry (IHC), are the biomarkers most frequently employed in clinical practice. In addition, microsatellite instability (MSI) was the first biomarker to demonstrate immunotherapy efficacy irrespective of the type of tumor and possesses a high predictive value. However, its limited use across most tumor types limits its therapeutic potential. This report describes two cancer patients with positive TMB and PD-L1 expression. The molecular profile of the tumor indicated that the first patient was responsive to Immune checkpoint inhibitors (ICI), while the second patient was resistant. These case studies demonstrate that tumor molecular analysis in combination with immunotherapy predictive biomarkers, such as PD-L1 expression and TMB, can enhance the prediction of response to ICI for specific patients. This methodology enables an individualized and improved approach to the treatment and management of the disease.

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FBXW7 attenuates tumor drug resistance and enhances the efficacy of immunotherapy

Cited by 5 publications

References 121 publications

5-Aza-2′-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential

5-Aza-2′-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential

MYCN in human development and diseases

Case report: Immunotherapy guided by molecular profiling of tumors: illustrative cases and literature review

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