Impact of Adding the Multikinase Inhibitor Sorafenib to Endocrine Therapy in Metastatic Estrogen Receptor-Positive Breast Cancer

Massarweh, Suleiman; Moss, Jessica; Wang, Chi; Romond, Edward H.; Slone, Stacey; Weiss, Heidi L.; Karabakhtsian, Rouzan G.; Napier, Dana; Black, Esther P.

doi:10.2217/fon.14.99

Cited by 10 publications

(4 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The addi-tion of sorafenib to endocrine therapy was generally welltolerated, with manageable toxicity, with most patients developing stable disease. [42] The rationale behind combining CDK 4/6 inhibitors with sorafenib or regorafenib is based on the potential synergistic effects of targeting multiple pathways involved in tumor growth. [20,43] Sorafenib and regorafenib inhibit the RAF/MEK/ERK signaling pathway, while CDK 4/6 inhibitors disrupt the cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

Overcoming Hormone Resistance in Breast Cancer Cell Lines: The Impact of Combined Treatment with Sorafenib and Palbociclib on Cell Survival and Proliferation Pathways

Almuradova

2024

EJMI

View full text Add to dashboard Cite

Objectives:The primary objective of this study was to investigate the potential synergy between Sorafenib, a multi-kinase inhibitor, and Palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, in the treatment of hormone receptor-positive breast cancer. Specifically, we aimed to determine whether the combination of these two drugs could enhance cell death in breast cancer cell lines. Methods: Cell Culture: Hormone receptor-positive breast cancer cell lines expressing estrogen receptors (ER-positive) and/or progesterone receptors (PR-positive) were selected for the study. Drug Treatment: Cells were treated with Sorafenib, Palbociclib, or a combination of both drugs. Cell Viability Assays: Cell viability and proliferation were assessed using MTT and BrdU assays, respectively. Immunoblotting: Protein expression and phosphorylation levels of key signaling molecules were analyzed to investigate the intracellular pathways affected by drug treatments. Statistical Analysis: Statistical comparisons were made between single-drug and combination-drug treatments to evaluate their effects on cell viability and proliferation. Results: Our study revealed the following key findings: Hormone receptor-positive breast cancer cells were chosen for this study due to their dependence on estrogen and progesterone for growth and division. Sorafenib, a multi-kinase inhibitor, effectively targeted multiple signaling pathways involved in cell proliferation, angiogenesis, and apoptosis, including Raf, VEGFR, PDGFR, and FLT3. Palbociclib, a CDK4/6 inhibitor, arrested cancer cells in the G1 phase of the cell cycle, preventing their progression into the S phase and subsequent proliferation. Contrary to expectations, the combination of Sorafenib and Palbociclib in hormone receptor-positive breast cancer cell lines did not result in enhanced cell death. Instead, it exhibited a proliferative effect. These unexpected results highlight the complexity of intracellular pathways and the potential for cross-talk between signaling pathways when drugs are combined. Conclusion:In conclusion, our study emphasizes the intricate and multifaceted nature of intracellular pathways in hormone receptor-positive breast cancer. The unanticipated proliferative effect of the Sorafenib and Palbociclib combination underscores the importance of considering all possible mechanisms of action when designing drug combinations for cancer treatment. This study serves as a valuable reminder that therapies should not solely depend on the modulation of a single pathway but rather take into account the intricate web of interactions within the cellular environment. Further research is warranted to elucidate the underlying molecular mechanisms responsible for the observed outcomes and to guide the development of more effective treatment strategies for hormone receptor-positive breast cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Overcoming Hormone Resistance in Breast Cancer Cell Lines: The Impact of Combined Treatment with Sorafenib and Palbociclib on Cell Survival and Proliferation Pathways

Almuradova

2024

EJMI

View full text Add to dashboard Cite

show abstract

“…Several clinical trials have been performed to evaluate sorafenib efficiency in prolonging patient survival; however, the results are controversial (32)(33)(34)(35)(36). Overall, the combination of sorafenib with chemotherapy or endocrine therapy has produced clinical improvements in patients.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Prognostic Significance of Vasculogenic Mimicry and Its Inhibition by Sorafenib in Canine Mammary Gland Tumors

et al. 2019

View full text Add to dashboard Cite

Canine mammary gland tumor (CMT) is one of the most important tumors in intact female dogs, and due its similarity to human breast cancer (BC), it is considered a model in comparative oncology. A subset of mammary gland tumors can show aggressive behavior, and a recurrent histological finding is the presence of vasculogenic mimicry (VM). VM is a process in which highly aggressive cancer cells fuse, forming fluid-conducting channels without endothelial cells. Although, VM has been described in canine inflammatory carcinoma, no previous studies have investigated the prognostic and predictive significance of VM in CMT. Thus, this research aimed to investigate the prognostic significance of VM in vivo and the capacity of sorafenib to inhibit VM in vitro. VM was identified in situ in formalin-fixed paraffin-embedded CMT samples (n = 248) using CD31/PAS double staining. VM was identified in 33% of tumors (82/248). The presence of VM was more strongly related to tumor grade than to histological subtype. Patients with positive VM experienced shorter survival times than dogs without VM (P < 0.0001). Due to the importance of the VEGF-A/VEGFR-2 autocrine feed-forward loop in epithelial tumors, we investigated the association between VEGF-A and VEGFR-2 expression by neoplastic tumor cells and the associations of VEGF-A or VEGFR-2 expression with VM. Among the VM-positive samples, all (n = 82) showed high scores (3 or 4) for VEGF-A and VEGFR-2, indicating that VM was a common finding in tumors overexpressing VEGF-A and VEGFR-2. Thus, we cultured two CMT primary cell lines with VM abilities (CM9 and CM60) in vitro and evaluated the anti-tumoral effect of sorafenib. The CM9 cell line showed a half maximal inhibitory concentration (IC 50) of 2.61 µM, and the CM60 cell line showed an IC 50 of 1.34 µM. We performed a VM assay in vitro and treated each cell line with an IC 50 dose of sorafenib, which was able to inhibit VM in vitro. Overall, our results indicated that VM was a prognostic factor for dogs bearing CMT and that sorafenib had an inhibitory effect on VM in CMT cancer cells in vitro.

show abstract

“…Combinations of first-and second-generation cytostatic drugs, novel targeted therapies including checkpoint inhibitors, multi-kinase inhibitors, and immunotherapies have resulted in remarkable progress in the treatment of non-visceral malignancies, including breast cancer, renal cancer, and malignant melanoma [1][2][3]. However, the prognosis remains poor for visceral malignancies e.g., liver, bile duct, and pancreas cancer, where most efforts so far have led to null or marginal efficacy.…”

Section: Introductionmentioning

confidence: 99%

A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma Cell Lines by Se-Methylselenocysteine

et al. 2021

View full text Add to dashboard Cite

Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. We evaluated a novel therapeutic regimen based on treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity, due to ROS formation, as compared to MSC alone. Furthermore, microRNA antisense-targeted sites for miR122, known to be widely expressed in normal hepatocytes while downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting the off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.

show abstract

Impact of Adding the Multikinase Inhibitor Sorafenib to Endocrine Therapy in Metastatic Estrogen Receptor-Positive Breast Cancer

Cited by 10 publications

References 43 publications

Overcoming Hormone Resistance in Breast Cancer Cell Lines: The Impact of Combined Treatment with Sorafenib and Palbociclib on Cell Survival and Proliferation Pathways

Overcoming Hormone Resistance in Breast Cancer Cell Lines: The Impact of Combined Treatment with Sorafenib and Palbociclib on Cell Survival and Proliferation Pathways

Investigation of the Prognostic Significance of Vasculogenic Mimicry and Its Inhibition by Sorafenib in Canine Mammary Gland Tumors

A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma Cell Lines by Se-Methylselenocysteine

Contact Info

Product

Resources

About