Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer

  title={Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer},
  author={Andrea Rocca and Alberto Farolfi and Sara Bravaccini and Alessio Schirone and Dino Amadori},
  journal={Expert Opinion on Pharmacotherapy},
  pages={407 - 420}
INTRODUCTION The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, governing the cell cycle restriction point, is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy. [] Key Method A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years. EXPERT OPINION The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials…

Updates on managing advanced breast cancer with palbociclib combination therapy

Palbociclib in combination with ET improved progression-free survival and QoL in patients with ABC, including in several patient subgroups.

The potential role of PD0332991 (Palbociclib) in the treatment of multiple myeloma

While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials.

CDK4/6 inhibitors in breast cancer

Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs.

Influence of PD-0332991 treatment on cell cycle regulatory genes in breast cancer stem cells

It was observed that PD-0332991 leads to different expression profiles for cell cycle regulatory genes between BCSCs and breast cancer cells.

Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA

The data support the efficacy of CDK 4 inhibitors against sarcomas displaying increased CDK4 levels, particularly fibrosarcomas and MPNST, and suggest that high levels of p16ink4a may indicate poor efficacy ofCDK4 inhibitors.

Oral adverse effects of CDK4/6 inhibitors among breast cancer patients: a systematic review and meta-analysis.

Prevention and management of CDK4/6Is-related stomatitis may effectively reduce its secondary impacts and specific quantitative impacts on patient quality of life and compliance require further questionnaire investigation.

Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer

These studies identified a novel series of mixedCDK2/PI3K inhibitors and demonstrate that dual targeting of CDK2 and PI3K can result in enhanced antitumour activity.

CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer

Surprisingly, response to CDK4/6 inhibition was highly variable in PDA models, and associated with differential suppression of gene expression, which provides a roadmap for combination therapies in the treatment of PDA.



Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991, indicating the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer.

It is suggested that suppression of cyclin D-supported kinase activity and restoration of RB-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies.

Antiestrogens, aromatase inhibitors, and apoptosis in breast cancer.

CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy

Evaluated studies suggest that while targeting the RB pathway represents a novel means of treatment in aggressive diseases such as TNBC, there should be a certain degree of caution when considering combination regimens of CDK4/6 inhibitors with genotoxic compounds that rely heavily on cell proliferation for their cytotoxic effects.

CDK4 Inhibitors and Apoptosis: A Novel Mechanism Requiring Nucleolar Targeting of RelA

The molecular mechanisms that regulate programmed cell death induced by disruption of the cyclin D1/CDK4 complex are discussed and the wider implications these findings have for the future development of novel chemotherapeutic agents are considered.

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

A role for CDK4/6 inhibition in some breast cancers is suggested and criteria for patient selection in clinical studies of PD 0332991 is identified.

The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer.

Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy, indicating that the RB pathway may represent a critical basis for directing therapy in the treatment of breast cancer.

Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.

Results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.

Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer.

  • T. MillerJ. BalkoC. Arteaga
  • Biology, Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2011
Altered alterations in the PI3K pathway associated with resistance to endocrine therapy, the state of clinical development ofPI3K inhibitors, and strategies for the clinical investigation of such drugs in hormone receptor-positive breast cancer are reviewed.

The CDK4/6 Inhibitor PD0332991 Reverses Epithelial Dysplasia Associated with Abnormal Activation of the Cyclin-CDK-Rb Pathway

CDK4 and phosphorylated pRb are distinguished as targets for chemoprevention regimens targeting reversal of hyperplasia and dysplasia following downregulation of the initiating viral oncoprotein Simian virus 40 (SV40) T antigen.