Novel RAF/MEK inhibitor CH5126766/VS‐6766 has efficacy in combination with eribulin for the treatment of triple‐negative breast cancer

Ono, Hisako; Horinaka, Mano; Sukeno, Mamiko; Morita, Masaru; Yasuda, Shusuke; Nishimoto, Emi; Konishi, Eiichi; Sakai, Toshiyuki

doi:10.1111/cas.15071

Cited by 6 publications

(5 citation statements)

References 43 publications

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“…Strong evidence for clinical translation of this agent into clinical trials was provided by its ability to suppress the growth of pre-established metastases in in vivo models [ 98 ]. Furthermore, a novel combination therapy comprising an RAF/MEK inhibitor CH5126766 (VS-6766) and eribulin has been demonstrated to potently inhibit TNBC cell line growth by inducing apoptosis and simultaneously suppressing the expression of the programmed cell death ligand 1 (PD-L1), with significant reduction in tumour growth in vivo [ 99 ] ( Figure 4 ).…”

Section: Novel Therapeutic Approaches For Tnbcmentioning

confidence: 99%

Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness

Mahmoud

Ordóñez‐Morán

Allegrucci

2022

Cancers

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The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which are not specific and do not target resistant cells. Therefore, one of the major clinical challenges is to find compounds that target the drug-resistant cell populations which are responsible for reforming secondary tumours. The molecular profiling of the different TNBC subtypes holds a promise for better defining these resistant cells specific to each tumour. To this end, a better understanding of TNBC heterogeneity and cancer stemness is required, and extensive genomic analysis can help to understand the disease complexity and distinguish new molecular drivers that can be targeted in the clinics. The use of persister cancer cell-targeting therapies combined with other therapies may provide a big advance to improve TNBC patients’ survival.

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Section: Novel Therapeutic Approaches For Tnbcmentioning

confidence: 99%

Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness

Mahmoud

Ordóñez‐Morán

Allegrucci

2022

Cancers

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“…Cancer patients with metastatic or locally advanced disease who participated in Phase I trials are presently being examined for Bay439006. 59 JNK/SAPK pathway inhibitor Small molecule drugs that target the JNK/SAPK MAPK pathway are being developed. In vitro, SP600125 inhibits JNK2 at 100 nm but not ERK, p38, or IB kinase (IKK) at micromolar doses.…”

Section: Raf Kinases In Cancer: Multifaceted Roles In Tumorigenesis A...mentioning

confidence: 99%

Exploring Small-Molecule Inhibitors Targeting MAPK Pathway Components: Focus on ERK, MEK1, and MEK2 Kinases in Cancer Treatment

Mukherjee,

Mohanty,

Kaur

et al. 2024

CBL

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Protein kinase cascades activate extracellular signal-regulated kinases (ERKs), or mitogen-activated protein kinases (MAPKs), which are involved in a variety of signal transduction pathways. This article will review the present state of MAPK pathway inhibitors, emphasizing the characteristics of tiny molecule blockers of the p38, MEK1, and MEK2 protein kinases. Many of these inhibitors have shown potential in experimental animal models of disease, and they are now being investigated in people for inflammatory and cancer diseases. Clinical trials are currently evaluating targeting a subset of cellular signaling cascades and signaling cascades that control pleiotropic cellular activity. These activities will have far-reaching consequences for managing a wide range of disorders. On the other hand, the Ras-Raf-MEK-ERK pathway is a clear therapeutic target because it is a standard downstream route for a range of critical growth factor tyrosine kinase receptors frequently changed or overexpressed in human malignancies. Several new medicines that target this route have been discovered and are currently being tested in clinical studies. BAY 43-9006 is one of the most intriguing new agents. Its ability to target Flt-3, c-Kit, and VEGFR-2, despite its initial development as a Raf kinase inhibitor, helps to explain its antiproliferative and antiangiogenic properties. This study will examine the ERK signaling pathway in both malignant and normal tissue, with an emphasis on new therapeutic approaches that target the ERK cascade at the Raf kinase level.

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“…A clinical trial in advanced cancer patients with the CI-1040 (an oral MEK inhibitor) shows the usual toxicities of CI-1040 were mild or moderate, like diarrhea, nausea, asthenia, and vomiting [ 65 ].Compared with solo therapy, combination therapy with MEK inhibitors seems to be more promising. The combination of CH5126766(RAF/MEK inhibitor) and eribulin was tested to potently inhibit cell growth in TNBC and to suppress the expression of programmed cell death-ligand 1 (PD-L1) [ 66 ]. A phase I/II study of AZD2014 (vistusertib, mTOR inhibitors) administered with selumetinib is carrying out a dose-escalation experiment in TNBC patients (NCT02583542).…”

Section: Receptor Tyrosine Kinases and Associated Pathwaysmentioning

confidence: 99%

Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy

Yang

Wang

et al. 2022

Mol Biomed

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Triple negative breast cancer (TNBC) is a subtype of breast cancer, with estrogen receptor, human epidermal growth factor receptor 2 and progesterone receptor negative. TNBC is characterized by high heterogeneity, high rates of metastasis, poor prognosis, and lack of therapeutic targets. Now the treatment of TNBC is still based on surgery and chemotherapy, which is effective only in initial stage but almost useless in advanced stage. And due to the lack of hormone target, hormonal therapies have little beneficial effects. In recent years, signaling pathways and receptor-specific targets have been reported to be effective in TNBC patients under specific clinical conditions. Now targeted therapies have been approved for many other cancers and even other subtypes of breast cancer, but treatment options for TNBC are still limited. Most of TNBC patients showed no response, which may be related to the heterogeneity of TNBC, therefore more effective treatments and predictive biomarkers are needed. In the present review, we summarize potential treatment opinions for TNBC based on the dysregulated receptors and signaling pathways, which play a significant role in multiple stages of TNBC development. We also focus on the application of immunotherapy in TNBC, and summarize the preclinical and clinical trials of therapy for patients with TNBC. We hope to accelerate the research and development of new drugs for TNBC by understanding the relevant mechanisms, and to improve survival.

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Novel RAF/MEK inhibitor CH5126766/VS‐6766 has efficacy in combination with eribulin for the treatment of triple‐negative breast cancer

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 6 publications

References 43 publications

Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness

Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness

Exploring Small-Molecule Inhibitors Targeting MAPK Pathway Components: Focus on ERK, MEK1, and MEK2 Kinases in Cancer Treatment

Therapeutic progress and challenges for triple negative breast cancer: targeted therapy and immunotherapy

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