Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer

Liang, Huaiyuan; Yang, Chunguang; Zeng, Ruijiang; Song, Yingqiu; Wang, Jianxi; Xiong, Wei; Yan, Binyuan; Jin, Xin

doi:10.1002/advs.202302368

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…Aberrant expression of CKS2 promotes prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death (42). EZH2, HMGB3, KIF2C, PKMYT1 and PLK1 have also been confirmed to be related to PRAD progression (43)(44)(45)(46)(47). Subsequently, we developed a diagnostic model for monocyte-related genes using machine learning techniques.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy

Wang,

Li,

et al. 2024

Front. Immunol.

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BackgroundMonocytes play a critical role in tumor initiation and progression, with their impact on prostate adenocarcinoma (PRAD) not yet fully understood. This study aimed to identify key monocyte-related genes and elucidate their mechanisms in PRAD.MethodUtilizing the TCGA-PRAD dataset, immune cell infiltration levels were assessed using CIBERSORT, and their correlation with patient prognosis was analyzed. The WGCNA method pinpointed 14 crucial monocyte-related genes. A diagnostic model focused on monocytes was developed using a combination of machine learning algorithms, while a prognostic model was created using the LASSO algorithm, both of which were validated. Random forest and gradient boosting machine singled out CCNA2 as the most significant gene related to prognosis in monocytes, with its function further investigated through gene enrichment analysis. Mendelian randomization analysis of the association of HLA-DR high-expressing monocytes with PRAD. Molecular docking was employed to assess the binding affinity of CCNA2 with targeted drugs for PRAD, and experimental validation confirmed the expression and prognostic value of CCNA2 in PRAD.ResultBased on the identification of 14 monocyte-related genes by WGCNA, we developed a diagnostic model for PRAD using a combination of multiple machine learning algorithms. Additionally, we constructed a prognostic model using the LASSO algorithm, both of which demonstrated excellent predictive capabilities. Analysis with random forest and gradient boosting machine algorithms further supported the potential prognostic value of CCNA2 in PRAD. Gene enrichment analysis revealed the association of CCNA2 with the regulation of cell cycle and cellular senescence in PRAD. Mendelian randomization analysis confirmed that monocytes expressing high levels of HLA-DR may promote PRAD. Molecular docking results suggested a strong affinity of CCNA2 for drugs targeting PRAD. Furthermore, immunohistochemistry experiments validated the upregulation of CCNA2 expression in PRAD and its correlation with patient prognosis.ConclusionOur findings offer new insights into monocyte heterogeneity and its role in PRAD. Furthermore, CCNA2 holds potential as a novel targeted drug for PRAD.

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Section: Discussionmentioning

confidence: 99%

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy

Wang,

Li,

et al. 2024

Front. Immunol.

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CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response

Hong,

Hogger,

Wang

et al. 2024

Cell Death Discov.

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CDK4/6 inhibitors are standard of care in the treatment of metastatic breast cancer. Treatment regimen consists of a combination with endocrine therapy, since their therapeutic efficacy as monotherapy in most clinical trials was rather limited. Thus, understanding the molecular mechanisms that underlie response to therapy might allow for the development of an improved therapy design. We analyzed the response to the CDK4/6 inhibitor palbociclib in bladder cancer cells over a 48-hour time course using RNA sequencing and identified a multi-step mechanism of response. We next translated these results to the molecular mechanism in bladder cancer cells upon PD treatment. The initial step is characterized by translocation of the RB protein into the nucleus by activation of importin α/β, a mechanism that requires the NLS sequence. In parallel, RB is proteolyzed in the cytoplasm, a process regulated by gankyrin and the SCF complex. Only hypophosphorylated RB accumulates in the nucleus, which is an essential step for an efficient therapy response by initiating G1 arrest. This might explain the poor response in RB negative or mutated patients. At later stages during therapy, increased expression of the MiT/TFE protein family leads to lysosomal biogenesis which is essential to maintain this response. Lastly, cancer cells either undergo senescence and apoptosis or develop mechanisms of resistance following CDK4/6 inhibition.

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Downregulation of UGT2B15 and UGT2B17 contributes to acquired androgen antagonist resistance in prostate cancer cells

Dart

2024

Academia Oncology

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Targeting CBX3 with a Dual BET/PLK1 Inhibitor Enhances the Antitumor Efficacy of CDK4/6 Inhibitors in Prostate Cancer

Cited by 3 publications

References 54 publications

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy

Multi-omics analysis and experimental validation of the value of monocyte-associated features in prostate cancer prognosis and immunotherapy

CDK4/6 inhibition initiates cell cycle arrest by nuclear translocation of RB and induces a multistep molecular response

Downregulation of UGT2B15 and UGT2B17 contributes to acquired androgen antagonist resistance in prostate cancer cells

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