Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma

Julve, Maximilian; Clark, James J.; Lythgoe, Mark P.

doi:10.1080/14656566.2020.1828348

Cited by 12 publications

(7 citation statements)

References 93 publications

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“…Cyclin-dependent kinase (CDKs) are a family of serine/threonine kinases with a regulatory role at checkpoints during the cell cycle, in combination with cyclin proteins. Hyper-activation of the CDK4/6-Rb-p16INK4A pathway is common and implicated in approximately 90% of melanomas [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

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Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Comito

Pagani

Grilli

et al. 2022

Cancers

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The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

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Section: Resultsmentioning

confidence: 99%

“…This immunomodulating effect could increase the efficacy of immunotherapy. Some promising results of efficacy have been shown in vitro and a phase I/II clinical trial of immunotherapy and CDK4/6 inhibitor combinations is underway (NCT02791334) [ 70 ].…”

Section: Resultsmentioning

confidence: 99%

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Comito

Pagani

Grilli

et al. 2022

Cancers

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“…Heretofore, several CDK4/6 inhibitors (e.g., Palbociclib ( Fry et al, 2004 ), Ribociclib ( Tripathy et al, 2017 ), and Abemaciclib ( Lee et al, 2019 )) have been approved by the FDA for the treatment of breast cancer and other solid tumors ( Yuan et al, 2021 ). However, the long-term use of CDK4/6 inhibitors results in drug resistance and poor therapeutic effect on Rb-deficient tumors, especially some malignant tumors, which limits the clinical application of CDK4/6 inhibitors ( Braal et al, 2021 ; Gomatou et al, 2021 ; Julve et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of 2-Aminopurine Derivatives as CDK2 Inhibitors for Triple-Negative Breast Cancer

et al. 2022

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Cyclin-dependent kinase 2 (CDK2) regulates the progression of the cell cycle and is critically associated with tumor growth. Selective CDK2 inhibition provides a potential therapeutic benefit against certain tumors. Purines and related heterocycle (e.g., R-Roscovitine) are important scaffolds in the development of CDK inhibitors. Herein, we designed a new series of 2-aminopurine derivatives based on the fragment-centric pocket mapping analysis of CDK2 crystal structure. Our results indicated that the introduction of polar substitution at the C-6 position of purine would be beneficial for CDK2 inhibition. Among them, compound 11l showed good CDK2 inhibitory activity (IC50 = 19 nM) and possessed good selectivity against other CDKs. Further in vitro tests indicated that compound 11l possesses anti-proliferation activity in triple-negative breast cancer (TNBC) cells. Moreover, molecular dynamics simulation suggested the favorable binding mode of compound 11l, which may serve as a new lead compound for the future development of CDK2 selective inhibitors.

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“…It is worth noticing that NRAS or BRAF mutation are frequent and associated with melanoma subtypes together with cyclin D1 and other factors [7]. Despite the advances in the treatment of malignant melanoma with BRAF/MEK targeted agents and immunotherapy, a poor prognosis for advanced disease is noted and therefore cyclin-dependent kinase inhibition either as single agent or in combination with established treatment are under clinical trials [8].…”

Section: Introductionmentioning

confidence: 99%

Lumican Inhibits In Vivo Melanoma Metastasis by Altering Matrix-Effectors and Invadopodia Markers

Καραμάνου

Franchi

Proult

et al. 2021

Cells

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It was reported that lumican inhibits the activity of metalloproteinase MMP-14 and melanoma cell migration in vitro and in vivo. Moreover, Snail triggers epithelial-to-mesenchymal transition and the metastatic potential of cancer cells. Therefore, the aim of this study was to examine the effect of lumican on Mock and Snail overexpressing melanoma B16F1 cells in vivo. Lung metastasis was analyzed after intravenous injections of Mock-B16F1 and Snail-B16F1 cells in Lum+/+ and Lum−/− mice. At day 14, mice were sacrificed, and lungs were collected. The number of lung metastatic nodules was significantly higher in mice injected with Snail-B16F1 cells as compared to mice injected with Mock-B16F1 cells confirming the pro-metastatic effect of Snail. This effect was stronger in Lum−/− mice as compared to Lum+/+, suggesting that endogenous lumican of wild-type mice significantly inhibits metastasis to lungs. Scanning electron and confocal microscopy investigations demonstrated that lumican inhibits the development of elongated cancer cell phenotypes which are known to develop invadopodia releasing MMPs. Moreover, lumican was shown to affect the expression of cyclin D1, cortactin, vinculin, hyaluronan synthase 2, heparanase, MMP-14 and the phosphorylation of FAK, AKT, p130 Cas and GSK3α/β. Altogether, these data demonstrated that lumican significantly inhibits lung metastasis in vivo, as well as cell invasion in vitro, suggesting that a lumican-based strategy targeting Snail-induced metastasis could be useful for melanoma treatment.

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Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma

Cited by 12 publications

References 93 publications

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Structure-Based Design of 2-Aminopurine Derivatives as CDK2 Inhibitors for Triple-Negative Breast Cancer

Lumican Inhibits In Vivo Melanoma Metastasis by Altering Matrix-Effectors and Invadopodia Markers

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