CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib, ribociclib, and abemaciclib

Cyclin-dependent kinases 4and 6(CDK4/6) are key regulators of the cell cycle,a nd there are FDA-approved CDK4/6 inhibitors for treating patients with metastatic breast cancer.H owever,d ue to conservation of their ATP-binding sites,d evelopment of selective agents has remained elusive. Here,w er eport imide-based degrader molecules capable of degrading both CDK4/6, or selectively degrading either CDK4 or CDK6. We were also able to tune the activity of these molecules against Ikaros (IKZF1) and Aiolos (IKZF3), which are well-established targets of imide-based degraders.W e found that in mantle cell lymphoma cell lines,c ombined IKZF1/3 degradation with dual CDK4/6 degradation produced enhanced anti-proliferative effects compared to CDK4/6 inhibition, CDK4/6 degradation, or IKZF1/3 degradation. In summary,w er eport here the first compounds capable of inducing selective degradation of CDK4 and CDK6 as tools to pharmacologically dissect their distinct biological functions.Cyclin-dependent kinases 4a nd 6( CDK4/6) regulate the G1-S cell-cycle transition by phosphorylating the tumor suppressor retinoblastoma (Rb), thereby triggering gene expression programs that promote S-phase entry. [1] As such, CDK4/6 are attractive targets for cancer therapy,and the dual CDK4/6 inhibitors palbociclib,r ibociclib,a nd abemaciclib have been FDAapproved for treating patients with advanced or metastatic breast cancer, leading to prolonged progressionfree-survival. [2] These agents are also currently under investigation in subsets of lung cancers,sarcomas,and lymphomas, such as mantle cell lymphoma (MCL), that exhibit aberrant cell-cycle progression due to activation of CDK4/6. [3] Although CDK4 and CDK6 are highly homologous, CDK4-and CDK6-specific functions have been reported. Fore xample,i namouse model of non-small-cell lung carcinoma, genetic ablation of CDK4 but not CDK6 induced senescence in lung cancer cells expressing mutant K-Ras. [4] On the other hand, CDK6-specific functions include participating as part of at ranscription complex that regulates expression of p16INK4a and VEGF-A, [5] and acting as ac o-factor for NFkB-dependent gene expression. [6] We also recently demonstrated that CDK6, but not CDK4, phosphorylates NFAT-family transcription factors to promote T-cell activation and enhance the antitumor immune response. [7] Since current CDK4/6 inhibitors target their highly conserved ATP-binding pockets and are approximately equipotent inhibitors of both proteins,w eh ypothesized that achieving selectivity would require exploiting selectivity determinants outside of the ATP-binding pocket. One approach is to develop small-molecule degraders,bifunctional molecules that consist of an E3 ubiquitin ligase binding moiety and at arget-binding moiety connected via an optimizable linker.S uccessful degradation requires induced heterodimerization between the E3 ligase and the target of interest, resulting in the targetsp olyubiquitination and subsequent proteasomal degradation. [8] This strategy has been deployed to achieve select...

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confidence: 99%

Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6

et al. 2019

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“…There is tremendous excitement about the clinical benefits of these agents. Currently, all three CDK4/6 inhibitors are approved (in combination with aromatase inhibitors) for the treatment of estrogen receptor-positive/HER2-negative metastatic breast cancer [186][187][188][189][190], and many clinical trials using these drugs are in progress for other types of cancer [191][192][193][194][195][196][197].…”

Section: Cdk-targeted Anti-cancer Therapymentioning

confidence: 99%

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

Kohlmeyer

Gordon

Tanas

et al. 2020

IJMS

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Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

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“…The approval of modern CDK inhibitors has changed the treatment paradigm for advanced HR+ cancer. The use of palbociclib, abemaciclib and ribociclib, that are selective reversible inhibitors of CDK4 and CDK6, has been approved based on progression free survival benefit seen on phase III studies (Laderian and Fojo, 2017). Except for ER positivity, no other biomarkers predictive of response to CDK4/6 inhibitors have been identified so far.…”

Section: Implication For Treatments In Breast Cancermentioning

confidence: 99%

Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications

Occhipinti¹,

Romagnoli

Santoni

et al. 2020

Front. Genet.

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About 75% of all breast cancers are hormone receptor-positive (HR+). However, the efficacy of endocrine therapy is limited due to the high rate of either pre-existing or acquired resistance. In this work we reconstructed the pathways around estrogen receptor (ER), mTOR, and cyclin D in order to compare the effects of CDK4/6 and PI3K/AKT/mTOR inhibitors. A positive feedback loop links mTOR and ER that support each other. We subsequently considered whether a combined or sequential inhibition of CDK4/6 and PI3K/AKT/mTOR could ensure better results. Studies indicate that inhibition of CDK4/6 activates mTOR as an escape mechanism to ensure cell proliferation. In literature, the little evidence dealing with this topic suggests that pretreatment with mTOR pathway inhibitors could prevent or delay the onset of CDK4/6 inhibitor resistance. Additional studies are needed in order to find biomarkers that can identify patients who will develop this resistance and in whom the sensitivity to CDK4/6 inhibitors can be restored.

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CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib, ribociclib, and abemaciclib

Cited by 64 publications

References 17 publications

Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6

Development of Dual and Selective Degraders of Cyclin‐Dependent Kinases 4 and 6

CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets

Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications

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