CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update

O’Sullivan, Ciara C.

doi:10.1080/14656566.2016.1201072

Cited by 12 publications

(6 citation statements)

References 76 publications

(59 reference statements)

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“…Thus far, this has been done more extensively with new antiandrogens 68,104 , but the generation and clinical observation of the L540Q ligand-activity inversion mutation in ERα after exposure to tamoxifen and the finding of other ERα activity-inversion mutations suggest that resistance to any structurally new antiestrogens through ERα LBD mutation should be screened for proactively. The general trend to combine antiestrogen endocrine therapies with other targeted-therapy agents, such as CDK4/6 inhibitors as well as other agents, may minimize the risk from different modes of therapy resistance 105–109 , including those due to mutations in ER.…”

Section: Discussionmentioning

confidence: 99%

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

et al. 2018

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Estrogen receptor alpha (ERα), a key driver of breast cancer, normally requires estrogen for activation. Mutations that constitutively activate ERα without the need for hormone are frequently found in endocrine therapy-resistant breast cancer metastases and are associated with poor patient outcomes. The location of these mutations in the ER ligand-binding domain and their impact on receptor conformation suggest that they subvert distinct mechanisms that normally maintain the low basal state of wild-type ERα in the absence of hormone. Such mutations provide opportunities to probe fundamental issues underlying ligand-mediated control of ERα activity. Instructive contrasts between these ER mutations and those that arise in androgen receptor (AR) during antiandrogen treatment of prostate cancer highlight differences in how activating functions in ER vs. AR control receptor activity, how hormonal pressures (deprivation vs. antagonism) drive the selection of phenotypically different mutants, and how altered protein conformations can reduce antagonist potency and altered ligand-receptor contacts can invert the response that a receptor has to an agonist vs. an antagonist. A deeper understanding of how ligand regulation of receptor conformation is linked to receptor function offers a conceptual framework for developing new antiestrogens that might be more effective in preventing and treating breast cancer.

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Section: Discussionmentioning

confidence: 99%

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

et al. 2018

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“…Nevertheless, we show that Palbociclib affects ER‐negative CMT cells, although ER expression is suggested to be a marker for Palbociclib responsiveness in hBCa cells . Since the approval of Palbociclib for treating ER‐positive/HER2‐negative hBCa, also oestrogen‐independent, pRb‐positive tumours turned out to be potential Palbociclib candidates, so that currently advanced urothelial cancer, squamous cell lung, pancreatic or head‐and‐neck tumours are under clinical trial (NCT02334527, NCT03065062). Moreover, Palbociclib has activity when combined with endocrine therapy in human patients with mammary tumours that are resistant to such therapy .…”

Section: Discussionmentioning

confidence: 72%

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

Schoos

Knab

Gabriel

et al. 2019

Vet Comparative Oncology

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Therapy of canine mammary tumours (CMTs) with classical antitumour drugs is problematic, so better therapeutic options are needed. Palbociclib (PD-0332991) is an innovative and effective anticancer drug for the treatment of breast cancer in women. Palbociclib is an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6, which are key regulators of the cell cycle machinery and thus cell proliferation. In the present in vitro study, we investigated whether Palbociclib also represents a candidate drug to combat CMT. For this purpose, the effect of Palbociclib was analysed in P114 and CF41 cells, two CMT cell lines with an endogenous CDK4/6 co-expression. Incubation of P114 and CF41 cells with Palbociclib resulted in a dose-and timedependent loss of phosphorylated retinoblastoma protein (pRb), a classical CDK4/6 substrate within the cell cycle machinery. Moreover, treatment of CMT cells with Palbociclib-induced cell cycle arrest affected cell viability, prevented colony formation and impaired cell migration activity. Palbociclib also inhibited the growth of P114 and CF41 cell spheroids. Immunohistochemical analysis of canine patient samples revealed a consistent expression of CDK6 in different canine mammary carcinoma types, but an individual and tumour-specific expression pattern of phosphorylated pRb independent of the tumour grade. Together, our findings let us suggest that Palbociclib has antitumour effects on CMT cells and that canine patients may represent potential candidates for treatment with this CDK4/6 inhibitor. K E Y W O R D S canine mammary tumour, CDK4/6, cell cycle, migration, Palbociclib

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“… 76 It has an average accumulated dose half-life (t1/2) of approximately 32 hours. 43 , 77 This long t1/2 enabled a once-daily dosing for the drug. 67 In addition, dose proportionality analyses over the dose range of 50–1,200 mg/day revealed that plasma concentration of ribociclib raised with the administered dose, with both peak concentration and area under the curve increasing slightly more than the proportion of dose increment.…”

Section: Methodsmentioning

confidence: 99%

“…Its metabolism is based mostly on the metabolic effects of cytochrome P450 (CYP) enzymes. 76 , 77 Consequently, drugs with inhibitory effects against CYP1A2 and CYP3A4 can affect excretion of the drug. 77 …”

Section: Methodsmentioning

confidence: 99%

Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib

Edessa¹,

Sisay

2017

BCTT

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In normal cell cycle progression, transition of G0/G1 phase to synthesis (S) phase for breast and other cells is regulated by association of cyclin D and cyclin-dependent kinases 4 and 6 (CDK4/6) that leads to phosphorylation of retinoblastoma (Rb) protein. Imbalance of this cyclin D-CDK4/6-inhibitors of CDK4/6-Rb phosphorylation pathway is associated with tumorigenesis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancers. Despite effective first-line endocrine therapy, HR+/HER2− metastatic breast cancers remain still incurable. Currently, advances in understanding of cell cycle checkpoints are evolving as promising strategy to target in treatment of various types of cancers including breast cancer. Therapies that target this cell cycle machinery in HR+/HER2− breast cancers are getting approval by the US Food and Drug administration (FDA) including ribociclib (LEE011). Ribociclib got the first FDA approval in March 13, 2017, as an initial therapy for HR+/HER2− advanced or metastatic breast cancer in combination with an aromatase inhibitor. This review, therefore, addresses the role of selective CDK4/6 inhibitors in advanced or metastatic breast cancer with a specific focus on ribociclib. Some findings of clinical trials involving ribociclib found pivotal benefits of ribociclib in HR+/HER2− metastatic breast cancer in terms of prolonging progression-free survival and objective response rates. Daily dosage range of the drug for such benefits is 50–900 mg with common daily doses of 400 or 600 mg and 600 mg in early and advanced breast cancer therapies, respectively. Along with its therapeutic benefits, however, more incident but manageable dose-limiting grade 3 or 4 toxicities, primarily hematologic adverse events, are common in patients treated with ribociclib. Generally, there are several active clinical trials undergoing to investigate the clinical efficacy and toxicity profile of the drug in various cancerous conditions other than breast cancer and will likely benefit patients with other cancer types.

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CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update

Abstract: In combination with endocrine therapy, CDK4/6i have shown promising efficacy in patients with advanced HR-positive, HER2-negative advanced breast cancer. Numerous trials in a variety of clinical settings and in different tumor types are ongoing or planned.

Cited by 12 publications

References 76 publications

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib

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CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update

Abstract: In combination with endocrine therapy, CDK4/6i have shown promising efficacy in patients with advanced HR-positive, HER2-negative advanced breast cancer. Numerous trials in a variety of clinical settings and in different tumor types are ongoing or planned.

Cited by 12 publications

References 76 publications

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2&minus; metastatic breast cancer: a focus on ribociclib

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Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib