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      Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib

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          Abstract

          Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib’s unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.

          Abstract

          This review provides a summary of recent preclinical data outlining molecular mechanisms by which CDK4 and 6 inhibitors exert their effects in cancer, with a focus on the unique attributes of abemaciclib.

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          Most cited references112

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          Breast Cancer Treatment

          Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer.
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            The senescence-associated secretory phenotype: the dark side of tumor suppression.

            Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
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              Palbociclib and Letrozole in Advanced Breast Cancer.

              Background A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. Methods In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety. Results The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole group and in 13 patients (5.9%) in the placebo-letrozole group. Conclusions Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .).
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                Author and article information

                Contributors
                Journal
                Oncologist
                Oncologist
                oncolo
                The Oncologist
                Oxford University Press (US )
                1083-7159
                1549-490X
                October 2022
                02 August 2022
                02 August 2022
                : 27
                : 10
                : 811-821
                Affiliations
                Department of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School , Boston, MA, USA
                Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA , Los Angeles, CA, USA
                Eli Lilly and Company , Indianapolis, IN, USA
                Eli Lilly and Company , Cork, Ireland
                Eli Lilly and Company , Indianapolis, IN, USA
                Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA , Los Angeles, CA, USA
                Department of Cancer Medicine, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia
                The Sir Peter MacCallum Department of Oncology, University of Melbourne , VIC, Australia
                Author notes
                Corresponding author: Shom Goel, B Med Sci (Hons), MBBS (Hons), FRACP, PhD, Department of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, 3000 Australia. Tel: +61 3 8559 8777; Fax: +61 3 8559 5039; Email: shom.goel@ 123456petermac.org
                Seth Wander, MD, PhD, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA. Email: swander@ 123456partners.org
                Author information
                https://orcid.org/0000-0002-1029-0596
                Article
                oyac138
                10.1093/oncolo/oyac138
                9526495
                35917168
                d030f5bc-c9fe-47d6-90bb-9a3de270732c
                © The Author(s) 2022. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

                History
                : 10 March 2022
                : 17 June 2022
                Page count
                Pages: 11
                Funding
                Funded by: Eli Lilly and Company, DOI 10.13039/100004312;
                Categories
                Academia-Pharma Intersect
                AcademicSubjects/MED00010

                Oncology & Radiotherapy
                abemaciclib,antitumor,breast neoplasms,cdk4 and 6,preclinical
                Oncology & Radiotherapy
                abemaciclib, antitumor, breast neoplasms, cdk4 and 6, preclinical

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