Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro.

Despite the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Bioinformatic analysis of obtained proteomics data indicated actin-cytoskeleton linker protein ezrin as a highly ranked protein significantly associated with vemurafenib resistance whose overexpression in the resistant cells was additionally confirmed at the gene and protein level. Ezrin inhibition by NSC305787 increased anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant cells in an additive manner, which was accompanied by downregulation of CD44 expression and inhibition of AKT/c-Myc activities. We also detected an increased ezrin expression in vemurafenib-resistant melanoma cells harbouring the BRAFV600E mutation. Importantly, ezrin inhibition potentiated anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant melanoma cells in a synergistic manner. Altogether, our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying the BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.

NSC305787, a pharmacological ezrin inhibitor, exhibits antineoplastic activity in pancreatic cancer cells.

Pancreatic cancer is one of the most lethal human neoplasms, and despite advances in the understanding of the molecular complexity involved in the development and progression of this disease, little of this new information has been translated into improvements in therapy and prognosis. Ezrin (EZR) is a protein that regulates multiple cellular functions, including cell proliferation, survival, morphogenesis, adhesion, and motility. In pancreatic cancer, EZR is highly expressed and reflects an unfavorable prognosis, whereas EZR silencing ameliorates the malignant phenotype of pancreatic cancer cells. NSC305787 was identified as a pharmacological EZR inhibitor with favorable pharmacokinetics and antineoplastic activity. Here, we endeavored to investigate the impact of EZR expression on survival outcomes and its associations with molecular and biological characteristics in The Cancer Genome Atlas pancreatic adenocarcinoma cohort. We also assessed the potential antineoplastic effects of NSC305787 in pancreatic cancer cell lines. High EZR expression was an independent predictor of worse survival outcomes. Functional genomics analysis indicated that EZR contributes to multiple cancer-related pathways, including PI3K/AKT/mTOR signaling, NOTCH signaling, estrogen-mediated signaling, and apoptosis. In pancreatic cells, NSC305787 reduced cell viability, clonal growth, and migration. Our exploratory molecular studies identified that NSC305787 modulates the expression and activation of key regulators of the cell cycle, proliferation, DNA damage, and apoptosis, favoring a tumor-suppressive molecular network. In conclusion, EZR expression is an independent prognosis marker in pancreatic cancer. Our study identifies a novel molecular axis underlying the antineoplastic activity of NSC305787 and provides insights into the development of therapeutic strategies for pancreatic cancer.

Ezrin is highly expressed and a druggable target in chronic lymphocytic leukemia.

AIMS: Despite the development of therapeutic strategies for chronic lymphocytic leukemia (CLL), most patients remain incurable, relapse, or refractory to current treatments, indicating the need to expand the antineoplastic repertoire for this disease. Ezrin (EZR) is a known oncogene in solid tumors and plays a key role in cell survival and BCR-mediated signaling activation in B-cell lymphomas. However, its role in hematological neoplasms remains poorly explored. MAIN METHODS: The present study assessed EZR expression in samples from CLL patients and healthy donors and evaluated the cellular and molecular effects of a pharmacological EZR inhibitor, NSC305787, in CLL cellular models. KEY FINDINGS: EZR was highly expressed and positively associated with relevant signaling pathways related to CLL development and progression, including TP53, PI3K/AKT/mTOR, NF-κB, and MAPK. NSC305787 reduced viability, clonogenicity, and cell cycle progression and induced apoptosis in CLL cells. Pharmacological EZR inhibition also attenuated ERK, S6RP, and NF-κB activation, indicating that EZR not only associates with but also activates these signaling pathways in CLL. Ex vivo assays revealed that the EZR inhibition-induced cell viability reduction was independent of molecular risk and the Binet stage. SIGNIFICANCE: Our study provides insights into EZR as a pharmacological target in CLL, shedding light on a novel strategy for treating this disease.