ribociclib and Triple-Negative-Breast-Neoplasms

Combination therapy with cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i: palbociclib, ribociclib, abemaciclib) and endocrine therapy (ET) has been a major advance for the treatment of hormone receptor-positive (HR+), ERBB2 (formerly HER2)-negative (ERBB2-) advanced or metastatic breast cancer.. Randomized phase 3 studies demonstrated that the addition of CDK4/6i reduced the hazard risk of disease progression by approximately half compared with hormonal monotherapy (an aromatase inhibitor, tamoxifen, or fulvestrant) in the first-line (1L) and/or second-line (2L) setting. Hence, the US Food and Drug Administration and European Medicines Agency approved 3 CDK4/6i, in both 1L and 2L settings. However, differences among the CDK4/6i regarding mechanisms of action, adverse effect profiles, and overall survival (OS) are emerging. Both abemaciclib and ribociclib have demonstrated efficacy in high-risk HR+ early breast cancer. While ET with or without CDK4/6i is accepted as standard treatment for persons with advanced HR+ ERBB2- metastatic breast cancer, several key issues remain. First, why are there discordances in OS in the metastatic setting and efficacy differences in the adjuvant setting? Additionally, apart from HR status, there are few biomarkers predictive of response to CDK4/6i plus ET, and these are not used routinely. Despite the clear OS advantage noted in the 1L and 2L metastatic setting with some CDK4/6i, a subset of patients with highly endocrine-sensitive disease do well with ET alone. Therefore, an unanswered question is whether some patients can postpone CDK4/6i until the 2L setting, particularly if financial toxicity is a concern. Finally, given the lack of endocrine responsiveness following progression on some CDK4/6i, strategies to optimally sequence treatment are needed.. Future research should focus on defining the role of each CDK4/6i in HR+ breast cancer and developing a biomarker-directed integration of these agents.

Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Protein Kinase Inhibitors; Receptor, ErbB-2; Triple Negative Breast Neoplasms

The triple-negative breast cancer (TNBC) subtype is the most aggressive type of breast cancer with a low survival prognosis and high recurrence rate. There is currently no effective treatment to improve it. In this work, we explored the effect of a synthetic compound named WXJ-103 on several aspects of TNBC biology. The human breast cancer cell lines MDA-MB-231 and MCF-7 were used in the experiments, and the cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, and the cell migration and invasion abilities were detected by wound healing assay and Transwell invasion assay. Cell cycle and apoptosis experiments were analyzed by flow cytometry, and protein levels related to cyclin-dependent kinase (CDK) 4/6-cyclin D-Rb-E2F pathway were analyzed by western blotting. Then, in-vivo experiments were performed to determine the clinical significance and functional role of WXJ-103. The results show that WXJ-103 can inhibit the adhesion, proliferation, migration, and invasion of TNBC cells, and can arrest the cell cycle in G1 phase. The levels of CDK4/6-cyclin D-Rb-E2F pathway-related proteins such as CDK6 and pRb decreased in a dose-dependent manner. Therefore, the antitumor activity of WXJ-103 may depend on the inhibition of CDK4/6-cyclin D1-Rb-E2F pathway. This research shows that WXJ-103 may be a new promising antitumor drug, which can play an antitumor effect on TNBC and provide new ideas for the treatment of TNBC.

Topics: Aminopyridines; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 4; Humans; Purines; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) that currently lacks specific therapy options. Thus, chemotherapy continues to be the primary treatment, and developing novel targets is a top clinical focus. The androgen receptor (AR) has emerged as a therapeutic target in a subtype of TNBC, with substantial clinical benefits shown in various clinical studies. Numerous studies have shown that cancer is associated with changes in components of the cell cycle machinery. Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are successful in the treatment of ER-positive BC, they are not helpful in the treatment of patients with TNBC. We investigated the possibility of combining CDK4/6 inhibitor(ribociclib) with AR inhibitor(enzalutamide) in the AR-positive TNBC cell line. Ribociclib showed an inhibitory effect in TNBC cells. Additionally, we found that enzalutamide reduced cell migration/invasion, clonogenic capacity, cell cycle progression, and cell growth in AR-positive cells. Enzalutamide therapy could increase the cytostatic impact of ribociclib in AR+ TNBC cells. Furthermore, dual inhibition of AR and CDK4/6 demonstrated synergy in an AR+ TNBC model compared to each treatment alone.

Topics: Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Protein Kinase Inhibitors; Receptors, Androgen; Triple Negative Breast Neoplasms

Topics: Aminopyridines; Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor Proteins; E2F1 Transcription Factor; Female; Humans; Male; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Phosphorylation; Purines; Retinoblastoma Protein; Triple Negative Breast Neoplasms; Tumor Burden

A third of patients with triple negative breast cancer (TNBC) have relapsed disease within 2-5 years from initial diagnosis, leaving an unmet need for therapeutic targets. TNBC frequently harbors alterations of the PI3K/AKT/mTOR pathway, but single agent PI3K/AKT/mTOR inhibitors have not shown marked efficacy. In this study, we investigated a strategy to improve efficacy of PI3K-α inhibitor BYL719 (alpelisib) in TNBC. While BYL719 is effective at inhibiting cell proliferation in T47D, a triple positive cell line, it had limited activity in TNBC. This may be partially due to persistent phosphorylation of RB, and incomplete inhibition of p-S6 in TNBC, since the inhibitory effect of BYL719 on p-RB and p-S6 was significantly reduced in TNBC compared to T47D cells. Addition of the CDK4/6 inhibitor LEE011 to BYL719 caused a simultaneous reduction of p-RB and p-S6, and a more complete inhibition of p-S6, leading to decreased expression of the pro-survival protein MCL-1, an induction of apoptosis, and an enhanced reduction of tumor growth in a PDX model of TNBC. These findings suggest that inhibition of p-RB and p-S6 is important for an effective response to the treatment of TNBC, and provides a strong rationale for clinical development of combination therapy with BYL719 and LEE011 for treatment of metastatic TNBC with intact RB.Presentation: This study was presented in part as an abstract at the 2016 San Antonio Breast Cancer Symposium (P3-03-15) and the 2018 Cancer Research and Targeted Therapy in London.

Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Synergism; Enzyme Inhibitors; Female; Humans; Mice; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Retinoblastoma Protein; Ribosomal Protein S6 Kinases; Signal Transduction; Thiazoles; TOR Serine-Threonine Kinases; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays