CDK4/6 Inhibition in Breast Cancer: Mechanisms of Response and Treatment Failure

Garrido-Castro, Ana C.; Goel, Shom

doi:10.1007/s12609-017-0232-0

Cited by 56 publications

(49 citation statements)

References 59 publications

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“…Deregulation of the Rb pathway and the expression of cyclin E1 (CCNE1) have been described as mediators of response to CDK4/6 inhibitors (21,28,29). Therefore, we analyzed the mRNA expression of RB1 and CCNE1, as well as a gene expression signature of Rb loss-of- (18,25,27).…”

Section: Response By Baseline Clinical Pathologic and Molecular Chamentioning

confidence: 99%

“…Studies of neoadjuvant ET demonstrated that a change in Ki67 after 2 weeks of therapy can be used as a pharmacodynamic marker of efficacy and correlated with recurrence-free survival (18)(19)(20). Aside from estrogen receptor status (ER þ ), predictive biomarkers of potential clinical benefit from CDK4/6 inhibitors remain elusive (21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

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Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Hurvitz

Martín

Press

et al. 2020

Clinical Cancer Research

135

112

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Purpose: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. Patients and Methods: Postmenopausal women with stage I-IIIB HR þ /HER2 À breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. Results: Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes. Conclusions: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR þ /HER2 À early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

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Section: Response By Baseline Clinical Pathologic and Molecular Chamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Hurvitz

Martín

Press

et al. 2020

Clinical Cancer Research

135

112

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“…Despite available knowledge of the CDK4/6 pathway, attempts to identify molecular biomarkers that predict response or resistance to CDK4/6 inhibitors in human breast cancers have failed to identify clear candidates. Putative biomarkers are discussed in detail elsewhere (see the work of Garrido-Castro and colleagues 63 ), and are summarized briefly here.…”

Section: Potential Biomarkers Of Response and Resistance To Cdk4/6 Inmentioning

confidence: 99%

CDK4/6 inhibition in breast cancer: current practice and future directions

et al. 2018

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The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)–retinoblastoma protein (RB) pathway plays a key role in the proliferation of both normal breast epithelium and breast cancer cells. A strong rationale for inhibiting CDK4/6 in breast cancers has been present for many years. However, potent and selective CDK4/6 inhibitors have only recently become available. These agents prevent phosphorylation of the RB tumor suppressor, thereby invoking cancer cell cycle arrest in G1. CDK4/6 inhibitors have transited rapidly from preclinical studies to the clinical arena, and three have already been approved for the treatment of advanced, estrogen receptor (ER)-positive breast cancer patients on account of striking clinical trial results demonstrating substantial improvements in progression-free survival. ER-positive breast cancers harbor several molecular features that would predict their sensitivity to CDK4/6 inhibitors. As physicians gain experience with using these agents in the clinic, new questions arise: are CDK4/6 inhibitors likely to be useful for patients with other subtypes of breast cancer? Are there other agents that could be effectively combined with CDK4/6 inhibitors, beyond endocrine therapy? Is there a rationale for combining CDK4/6 inhibitors with novel immune-based therapies? In this review, we describe not only the clinical data available to date, but also the biology of the CDK4/6 pathway and discuss answers to these questions. In particular, we highlight that CDK4 and CDK6 govern much more than the cancer cell cycle, and that their optimal use in the clinic depends on a deeper understanding of the less well characterized effects of these enzymes.

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“…CDK4/6 can phosphorylate Rb, a tumor suppressor involved in cell cycle regulation (Gao et al, 2018). Rb expression in cancerous tissues is higher than it is in healthy tissues and is correlated with a poor prognosis (Garrido-Castro & Goel, 2017;Singh, Malik, Goswami, Shukla, & Kaur, 2016). The Rb-E2F1 complex is released upon Rb phosphorylation and is associated with the modulation of gene transcription and stimulation of cell proliferation (Mushtaq, Gaza, & Kashuba, 2016).…”

Section: Discussionmentioning

confidence: 99%

CDK4/6 inhibitor protects chemerin‐induced human granulosa‐lutein cells from apoptosis by inhibiting the p53/p21^waf pathway

Liu

Zhang

Shan

et al. 2019

Molecular Reproduction Devel

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Dysregulation of the cell cycle is common in human tumorigenesis. Therefore, CDK4/6 inhibitors targeting the cell cycle have been developed, and their antiapoptotic effects have been highly correlated with potential clinical therapies. The aim of this study was to identify the regulatory effect of the CDK4/6 inhibitor palbociclib on chemerin‐induced apoptosis of immortalized human granulosa‐lutein (hGL) cells and to elucidate its fundamental mechanism of action. Palbociclib enhanced antioxidative enzyme generation and diminished ROS generation in hGL cells. Furthermore, we found that palbociclib suppressed chemerin‐induced apoptotic protein expression, reversing the Bcl‐2/Bax ratio and inhibiting the p53/p21 waf pathway. Eventually, palbociclib decreased the level of cleaved caspase‐3 and ‐9, hindering the apoptosis of hGL cells. In general, the antiapoptotic efficacy of palbociclib could be attributed in part to the modulation of the mitochondrial apoptotic pathway in hGL cells.

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CDK4/6 Inhibition in Breast Cancer: Mechanisms of Response and Treatment Failure

Cited by 56 publications

References 59 publications

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

CDK4/6 inhibition in breast cancer: current practice and future directions

CDK4/6 inhibitor protects chemerin‐induced human granulosa‐lutein cells from apoptosis by inhibiting the p53/p21^waf pathway

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CDK4/6 Inhibition in Breast Cancer: Mechanisms of Response and Treatment Failure

Cited by 56 publications

References 59 publications

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

CDK4/6 inhibition in breast cancer: current practice and future directions

CDK4/6 inhibitor protects chemerin‐induced human granulosa‐lutein cells from apoptosis by inhibiting the p53/p21waf pathway

Contact Info

Product

Resources

About

CDK4/6 inhibitor protects chemerin‐induced human granulosa‐lutein cells from apoptosis by inhibiting the p53/p21^waf pathway