A clinical evaluation of treatments that target cell cycle machinery in breast cancer.

A clinical evaluation of treatments that target cell cycle machinery in breast cancer. Expert Opin Pharmacother. 2019 Oct 14;:1-11 Authors: Fedele P, Sanna V, Fancellu A, Cinieri S Abstract Introduction: The dysregulation of cell cycle control can lead to cancer development. In breast cancer, cyclin D, CDK 4,6 and the retinoblastoma protein play a central role in the control of cell proliferation, in crosstalk with the estrogen receptor and Her2 pathways. Although the mechanisms by which the CDK4/6 complex is involved in the control of cell growth in triple negative breast cancer (TNBC) are still unclear, some TNBCs might be sensitive to CDK4/6 inhibitors. Areas covered: The authors provide an overview of the treatments that target cell cycle machinery in breast cancer and provide their perspectives for the future. Expert opinion: CDK 4/6 inhibitors are active drugs in HR+ MBC, but some unresolved issues remain. We need to identify biomarkers of response. Moreover, we need to determine the optimal timing for the incorporation of CDK 4/6 inhibitors in the current treatment algorithm. In the Her2 positive subtype, the triple combination of anti Her2 therapies with CDK4/6 inhibitors and endocrine therapy seems to be a promising chemotherapy free approach. Efforts must still be made for the treatment of the TNBC subtype, even though new CDK 4/6 combinations are emerging as promising approaches to selected patients. PMID: 31610139 [PubMed - as supplied by ...
Source: Expert Opinion on Pharmacotherapy - Category: Drugs & Pharmacology Tags: Expert Opin Pharmacother Source Type: research

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AbstractBackgroundHER2 blockade in combination with chemotherapy (CT) remains the treatment of choice for patients with early HER2+ BC, irrespective of ER status. Patients with HER2+ early BC co-expressing ER may benefit from HER2 blockade in combination with endocrine therapy (ET) and new targeted agents. Elderly patients benefit from HER2 blockade as much as younger ones but they have higher risks of adverse events, mostly induced by the CT partner, making de-escalation of CT appealing. Recent data have elucidated cyclin-dependent kinases 4 and 6 (CDK4/6) as key therapeutic targets functioning downstream of both ER and H...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
Conclusions In the new era of targeted therapy, treatment options are increasingly based on the precise molecular and genetic profiling of tumor cells (58). Currently, the main challenge for further novel drug development in targeted therapy is the clarification of specific molecular mechanisms underlying the varied forms of tumors in clinic. It has been acknowledged that cancer is caused by a set of driver mutations. In this regard, it is of great significance to: (1) identify and validate key mutant genes and proteins in cancers as new targets; (2) identify patients most likely and unlikely to benefit from certain targe...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
ConclusionsWe revealed that palbociclib and MLN0128 had synergistic anti-cancer activity in both pRb  + ER-negative cell lines and a TNBC PDX model. Our results indicate that such combination therapy is worthy of further investigation in a clinical setting.
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
Conclusion: CDK4/6 inhibitors exhibit a high therapeutic potential, although reliable prognostic markers need to be identified.Breast Care
Source: Breast Care - Category: Cancer & Oncology Source Type: research
Contributors : Mayumi Harada ; Masato Morikawa ; Takayuki Ozawa ; Yusuke Tamura ; Kohei Miyazono ; Daizo KoinumaSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensInhibitors for cyclin-dependent kinase (CDK) 4 and CDK6 have been established as effective therapeutic options for hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Although the CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we have f...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Source Type: research
Contributors : Mayumi Harada ; Masato Morikawa ; Takayuki Ozawa ; Yusuke Tamura ; Kohei Miyazono ; Daizo KoinumaSeries Type : Genome binding/occupancy profiling by high throughput sequencingOrganism : Homo sapiensInhibitors for cyclin-dependent kinase (CDK) 4 and CDK6 have been established as effective therapeutic options for hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Although the CDK4/6 inhibitors mainly target the cyclin D-CDK4/6-retinoblastoma tumor suppressor protein (RB) axis, little is known about clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we have f...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Genome binding/occupancy profiling by high throughput sequencing Homo sapiens Source Type: research
CONCLUSIONS: Abemaciclib is an effective and well-tolerated treatment for HR-positive, HER2-negative advanced or metastatic breast cancer. PMID: 30099886 [PubMed - as supplied by publisher]
Source: The Annals of Pharmacotherapy - Category: Drugs & Pharmacology Authors: Tags: Ann Pharmacother Source Type: research
ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer. Oncotarget. 2018 Jun 12;9(45):27736-27751 Authors: Petrossian K, Kanaya N, Lo C, Hsu PY, Nguyen D, Yang L, Yang L, Warden C, Wu X, Pillai R, Bernal L, Huang CS, Kruper L, Yuan Y, Somlo G, Mortimer J, Chen S Abstract While ER has multiple biological effects, ER-cyclin D1-CDK4/6-RB is a critical pathway for the action of estrogen on the cell cycle, especially for breast cancers that rely on estrogen for growth. The latest and most efficient CDK4/6 inhibitors target the phosphorylation o...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Cyclin dependent kinase (CDK) 4/6 inhibitors have advanced the treatment of metastatic breast cancer by targeting the cell cycle machinery, interrupting intracellular and mitogenic hormone signals that stimulate proliferation of malignant cells. Preclinical evidence demonstrated that derangements of cyclin D1, CDK4/6 and retinoblastoma expression are common in breast cancer, and suggested a therapeutic benefit from interrupting this axis required for cell cycle progression. Studies of cell lines and animal models of breast cancer have demonstrated the complex interplay between the cell cycle and estrogen receptor (ER) and ...
Source: Seminars in Oncology - Category: Cancer & Oncology Authors: Source Type: research
Targeting the estrogen-receptor signalling pathway represented for many decades the standard of care for both locally and advanced hormone receptor positive (HR+) breast cancer. Deregulation of cyclin-D/cyclin-dependent kinase 4/6/retinoblastoma gene product pathway is implicated in resistance to endocrine therapy (ET). Three randomized trials showed that adding the CDK inhibitors (CDKi) palbociclib/ribociclib to letrozole significantly improved progression-free survival (PFS) than letrozole in upfront treatment of postmenopausal women with advanced HR+/Her2 − breast cancer [1 –3]. Moreover, combining palbocicl...
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
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