CDK4: A Novel Therapeutic Target for Extramammary Paget’s Disease

Hashimoto, H.; Kaku-Ito, Yumiko; Oda, Yoshinao; Ito, Takamichi

doi:10.3389/fonc.2021.710378

Cited by 5 publications

(5 citation statements)

References 52 publications

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“…There is thus a strong need to identify appropriate therapeutic targets and develop more efficacious therapies. Although intensive efforts in pursuit of a novel therapeutic target have been made, [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] such work has mostly been limited to immunohistochemical studies; functional analyses using a cell line or other disease models are required to corroborate the obtained results. [46][47][48] Cancer cell lines are essential tools to screen potential therapeutic targets of cancer, but the analysis of EMPD has been largely limited by the lack of EMPD cell lines maintainable in conventional two-dimensional culture systems.…”

Section: Discussionmentioning

confidence: 99%

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NECTIN4‐targeted antibody–drug conjugate is a potential therapeutic option for extramammary Paget disease

Tanaka,

Ito,

Murata

et al. 2024

Experimental Dermatology

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Extramammary Paget disease (EMPD) is a rare skin cancer mainly found in areas rich in apocrine sweat glands. Since the effective treatments for advanced and/or metastasized EMPD are limited, there is an urgent need to develop novel therapeutic approaches. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in cancers and considered to be a promising therapeutic target. NECTIN4 is also expressed in EMPD, but its role and the efficacy of NECTIN4‐targeted therapy in EMPD remain unclear. This study investigated the potential of NECTIN4 as a novel therapeutic target for EMPD. NECTIN4 expression was immunohistochemically analysed in EMPD patients' primary (118 samples) and metastatic (21 samples) lesions. Using an EMPD cell line, KS‐EMPD‐1, the effects of NECTIN4 inhibition on cell proliferation and migration were investigated. NECTIN4 was expressed in primary and metastatic EMPD lesions, and the H‐score of NECTIN4 staining was significantly higher in metastatic lesions than in primary ones. Knockdown of NECTIN4 significantly inhibited cell proliferation and affected cell migration. The cytotoxic effects of NECTIN4‐targeted antibody–drug conjugate (ADC) were further evaluated, revealing a significant decrease in EMPD cell viability. In conclusion, NECTIN4 is a potential therapeutic target and NECTIN4‐targeted ADC is promising as a therapeutic option for EMPD.

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Section: Discussionmentioning

confidence: 99%

“…these drugs is low and a large number of patients do not respond to them, so the prognosis remains poor. [10][11][12][13] Although intensive efforts have been made to identify potential therapeutic targets for EMPD, [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] there is an urgent need to develop other highly effective drugs.…”

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confidence: 99%

NECTIN4‐targeted antibody–drug conjugate is a potential therapeutic option for extramammary Paget disease

Tanaka,

Ito,

Murata

et al. 2024

Experimental Dermatology

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“…trials are also being conducted for a variety of locally advanced or metastatic malignancies with deletions of CDKN2A. 31,32 A few studies have reported that CDK4/6 inhibitors are effective for EMPD with distant metastasis [41][42][43] ; thus, advanced EMPD with CDKN2A deletions is an indication for CDK4/6 inhibitor therapy. Immunohistochemical findings of p16 loss can serve as an indicator for evaluating the suitability of CDK4/6 inhibitors in EMPD.…”

Section: Discussionmentioning

confidence: 99%

Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases

Hiraki,

Oishi,

Yoshikawa

et al. 2024

The American Journal of Dermatopathology

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Information regarding the genetic alterations in extramammary Paget disease (EMPD) is scarce. This study investigated the significance of CDKN2A and MTAP alterations in EMPD progression using immunohistochemistry and panel DNA sequencing. In total, 24 invasive/metastatic EMPD cases were included in this study. The immunoexpression of p16 and MTAP in the primary in situ, primary invasive, and metastatic tumor components was evaluated. Panel DNA sequencing was performed for metastatic tumor components in 5 of the 24 cases. Immunoexpression of p16 in the in situ tumor component was at least partially preserved in all 19 tested cases (100%). By contrast, the invasive tumor component was diffusely or partially lost in 18 (81.8%) of 22 tested cases. Regarding the foci of lymph node metastasis, 13 (81.2%) of the 16 patients showed a significant loss of p16 expression. Loss of MTAP immunoexpression was observed less frequently compared with the loss of p16 expression. CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.

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“…CDK4 was identified as a major risk factor for disease progression in Paget’s disease [ 375 ] and its overexpression and/or hyperactivation is implicated in many types of human cancers [ 376 , 377 , 378 , 379 , 380 , 381 ]. Point mutations at the CDK4 locus (CDK4R24C) have also been reported [ 382 ].…”

Section: Protein Kinases In Pediatric Oncology and Their Association ...mentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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CDK4: A Novel Therapeutic Target for Extramammary Paget’s Disease

Cited by 5 publications

References 52 publications

NECTIN4‐targeted antibody–drug conjugate is a potential therapeutic option for extramammary Paget disease

NECTIN4‐targeted antibody–drug conjugate is a potential therapeutic option for extramammary Paget disease

Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

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