INTERNATIONAL CONGRESS OF
PharmacoGenetics
Therapeutic Role of Palbociclib as a Cyclin-Dependent Kinase Inhibitor in Triple-Negative Breast Cancer
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Mehrdad Ostadpoor,1,* Ahmad Zeinodini,2 Seyyed Hossein Heidari,3
1. Graduated of Veterinary Medicine Faculty, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
2. Graduated of Veterinary Medicine Faculty, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
3. Graduated of Veterinary Medicine Faculty, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
- Introduction: Breast cancer (BC) is the most commonly diagnosed cancer among women and the second leading cause of cancer-related mortality worldwide. Based on molecular markers, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), BC is categorized into three major subtypes: hormone receptor (HR)-positive, HER2-positive, and triple-negative breast cancer (TNBC). TNBC accounts for approximately 15% to 20% of all breast carcinomas. Dysregulation of cellular proliferation is a feature of all human cancers, and the maintenance of abnormal proliferative signals is a key marker for cancer. The main function of inhibitors is to block cell cycle and inhibit cell proliferation by inhibiting the Cyclin-dependent kinase (CDK) enzyme activity. In this pathway, cyclin D1 forms an activating complex with CDK 4 and CDK6 that go on to phosphorylate the retinoblastoma protein (Rb). Palbociclib, a selective CDK1, exerts its killing effect on tumor cells rather than on normal cells.
- Methods: In the current study, keywords including Palbociclib, Cyclin-Dependent Kinase Inhibitor, and Triple-Negative Breast Cancer were reviewed from the list of Mesh and other credible websites including PubMed, Science Direct and Google Scholar and the data was organized. The searches comprised all published paper from 2010 to 2023. All of full text was considered and the papers manifested as only abstract was excluded. The full papers selected that specific role of Therapeutic Role of Palbociclib as a Cyclin-Dependent Kinase Inhibitor in Triple-Negative Breast Cancer only. Totally 50 papers were selected and studied in this review.
- Results: Evidences showed inhibition of CDK4 decreased the percentage of chemotherapy-resistant cells and breast cancer stem cells in TNBC. Several preclinical studies have evaluated palbociclib, a CDK4/6 inhibitor, together with a second-generation dual mTOR kinase inhibitor MLN0128, has demonstrated a cooperative suppressed tumor growth effect in retinoblastoma protein expressing TNBC patient-derived tumor xenograft (PDX) tumors. Moreover CDK4/6 inhibitors can inhibit Rb phosphorylation to prevent the proliferation of tumor cells. One study showed palbociclib to significantly reduce the cell proliferation rate of several aggressive basal-like TNBC cell lines (SUM159, MDA-MB231, and SCP2). Other study reavelant that blocking CDK4 kinase activity using palbociclib reduced breast cancer stem cells numbers and their self-renewal capacity in TNBCs. In vivo trials, palbociclib caused a sustained suppression of tumor Rb phosphorylation, and exhibited significant antitumor efficacy that arrested Rb-positive tumors exclusively in G1, including Rb-positive breast cancer. In addition, synergistic activity between cell cycle and anti-estrogen therapies had been observed in breast cancer cell lines. In the following tumor cell lines, such as MDA-MB-231 and more significant levels in MCF-7 cells, Rb deficiency produced a very significant growth advantage in the presence of palbociclib, which had been observed to increase levels of E2F-target genes cyclins A and E.
- Conclusion: Inhibition of CDKs inactivates the G1 transcription factor and E2F during. Because the CDK4/6 plays an important role in the development and progression of breast cancer, CDK4/6 inhibitors have revolutionized the treatment of metastatic breast cancer. In combination with endocrine therapies, CDK4/6 inhibitors have become a new standard of care for patients with ER-positive breast cancer.
- Keywords: Palbociclib, Cyclin-Dependent Kinase Inhibitor, Triple-Negative Breast Cancer
