Progress with palbociclib in breast cancer: latest evidence and clinical considerations

Abstract

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HRpositive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

Microtubules play an essential role in the survival of primary acute lymphoblastic leukemia cells advancing through G1 phase

“…A leading candidate is the highly selective CDK4/6 inhibitor palbociclib (PCB) [24]. PCB received accelerated approval for use in combination with the aromatase inhibitor letrozole or the estrogen receptor antagonist fulvestrant for patients with metastatic HR-positive and HER2-negative breast cancer, and has shown activity in combination with radiotherapy for glioblastoma [25][26][27][28][29]. In this study, we show that PCB has a cytostatic effect on ALL cells, causing G1 phase arrest without reducing viability.…”

Targeting the cell cycle in breast cancer: towards the next phase

“…Together, these findings suggested the cyclin D-CDK4/6 axis could be a promising therapeutic target with a breast cancerspecific therapeutic window, and spurred the development of CDK4/6 specific inhibitors. Three ATPcompetitive inhibitors (palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219)) have recently been evaluated in clinical trials in combination with standard endocrine therapies in metastatic breast cancer, and have demonstrated significant improvements in tumor response rate and progression-free survival compared to endocrine therapy alone, which has led to their FDA approvals in combination with aromatase inhibitors or fulvestrant [39][40][41]. In addition to these approved compounds, several other CDK4/6 inhibitors are being evaluated in clinical trials as combination therapies with standard chemotherapies in breast and other malignancies (e.g.…”

Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases

“…Several potent, selective inhibitors targeting CDK4/6 (CDK4/6is) have undergone clinical trials including palbociclib (PD0332991), abemaciclib (LY-2835219) and ribociclib (LEE001) [6,7], and have gained regulatory approval in combination with hormonal therapy in breast cancer [8][9][10][11]. However, evidence for clinical benefit has not been extended to other cancer types thus far, and relapse under therapy is frequent in the approved indication in breast cancer [9]. Activation of CDK4/6 requires their binding to D-type cyclins, synthesised in response to mitogenic signals [12,13].…”