MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

Portman, Neil; Chen, Julia; Lim, Elgene

doi:10.3389/fonc.2021.777867

Cited by 6 publications

(5 citation statements)

References 93 publications

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“…2 A, B, Table 1 ). Moreover, although CDK4 and MDM2 have been demonstrated to be involved in lung cancer, their roles as therapeutic targets have not yet been firmly established [ 30 ]. Regardless, they were ranked the most prominent in this assessment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Translating our findings from WGS and ChIP-seq analyses for clinical applications requires prospective trials. By applying our method, we identified a preponderance of probable driver genes, some of which are currently under clinical investigation [ 30 , 56 – 59 ]. This approach offers significant benefits for patient selection and potentially improves the efficacy of clinical trials by targeting individuals with relevant genetic profile.…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations

Kaneko,

Takasawa,

Asada

et al. 2024

Mol Cancer

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Background In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. Methods We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. Results We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. Conclusions Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations

Kaneko,

Takasawa,

Asada

et al. 2024

Mol Cancer

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“…MDM2 overexpression leads to interruption of cell senescence and hence CDK4/6is resistance. For this reason, MDM2 inhibitors may be useful in treating patients' resistant to CDK4/6is, despite further studies being needed [39].…”

Section: Mdm2 Overexpressionmentioning

confidence: 99%

Progression after First-Line Cyclin-Dependent Kinase 4/6 Inhibitor Treatment: Analysis of Molecular Mechanisms and Clinical Data

Villa,

Crippa,

Pelizzoni

et al. 2023

IJMS

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Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance to CDK4/6is, as well as treatment strategies and the clinical data about the efficacy of subsequent treatments after CDK4/6is-based therapy. In the first part, this review mainly discusses cell-cycle-specific and cell-cycle-non-specific resistance to CDK4/6is, with a focus on early and late progression. In the second part, this review analyzes potential therapeutic approaches and the available clinical data on them: switching to other CDK4/6is, to another single hormonal therapy, to other target therapies (PI3K, mTOR and AKT) and to chemotherapy.

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“…[90][91][92] Role of SIPL1/SHARPIN in BC oncogenesis, especially ER+ BC, has not been thoroughly studied until recent years. It has been reported that overexpression of SIPL1/SHARPIN in BC cells reduces p53 protein levels and p53 target genes MDM2, 93 P21, P53INP1, and BTG2, and increases activity of MAPK and AMPK pathways, 94,95 leading to resistance to TAM through AKT activation and NF-kB signaling pathways. 96,97 Various oncogenic miRNAs regulated by estrogen/ERα interaction signaling have been found to cause endocrine drug resistance during treatments.…”

Section: Other Er-mediated Endocrine Therapy Resistance Pathwaysmentioning

confidence: 99%

Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer

Song

Lin

2022

Technol Cancer Res Treat

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In estrogen receptor positive (ER+) breast cancer therapy, estrogen receptors (ERs) are the major targeting molecules. ER-targeted therapy has provided clinical benefits for approximately 70% of all breast cancer patients through targeting the ERα subtype. In recent years, mechanisms underlying breast cancer occurrence and progression have been extensively studied and largely clarified. The PI3K/AKT/mTOR pathway, microRNA regulation, and other ER downstream signaling pathways are found to be the effective therapeutic targets in ER+ BC therapy. A number of the ER+ (ER+) breast cancer biomarkers have been established for diagnosis and prognosis. The ESR1 gene mutations that lead to endocrine therapy resistance in ER+ breast cancer had been identified. Mutations in the ligand-binding domain of ERα which encoded by ESR1 gene occur in most cases. The targeted drugs combined with endocrine therapy have been developed to improve the therapeutic efficacy of ER+ breast cancer, particularly the endocrine therapy resistance ER+ breast cancer. The combination therapy has been demonstrated to be superior to monotherapy in overall clinical evaluation. In this review, we focus on recent progress in studies on ERs and related clinical applications for targeted therapy and provide a perspective view for therapy of ER+ breast cancer.

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MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

Cited by 6 publications

References 93 publications

Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations

Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations

Progression after First-Line Cyclin-Dependent Kinase 4/6 Inhibitor Treatment: Analysis of Molecular Mechanisms and Clinical Data

Estrogen Receptor Bio-Activities Determine Clinical Endocrine Treatment Options in Estrogen Receptor-Positive Breast Cancer

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