Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively d...
Regardless of the significant improvements in treatment of melanoma, the majority of patients develop resistance whose mechanisms are still not completely understood. Hence, we generated and characterized two melanoma-derived cell lines, primary WM79...
(1) BRAF mutations are associated with high mortality and are a substantial factor in therapeutic decisions. Therapies targeting BRAF-mutated tumors, such as vemurafenib (PLX), have significantly improved the overall survival of melanoma patients. Ho...
Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH)...
The development of targeted therapies (BRAF/MEK inhibitors) and immunotherapy have had a major impact on the treatment of melanoma. However, the majority of patients with advanced melanomas succumb to their disease. The mechanisms of resistance to bo...
Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather q...
A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a s...
Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MA...
The clinical outcomes of malignant melanoma have improved with the introduction of mitogen-activated protein kinase kinase (MEK) inhibitors. However, off-target toxicities of the MEK inhibitor trametinib (TMB) often result in dose interruption and di...
Background: Despite recent improvements in therapy, the five-year survival rate for patients with advanced melanoma is poor, mainly due to the development of drug resistance. The aim of the present study was to investigate the mechanisms underlying t...
Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most freque...
The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal r...
Background: Previously, we have demonstrated that nuclear BRAFV600E is associated with melanoma aggressiveness and vemurafenib resistance. However, the underlying mechanisms of how nuclear localization of BRAFV600E promotes cell aggressiveness have n...
Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies target...
We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferat...
Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were deve...
Targeted therapy resistance frequently develops in melanoma due to intratumor heterogeneity and epigenetic reprogramming. This also typically induces cross-resistance to immunotherapies. Whether this includes additional modes of therapy has not been...
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 resist...
Activating BRAF mutations occurs in 50–60% of malignant melanomas. Although initially treatable, the development of resistance to BRAF-targeted therapies (BRAFi) is a major challenge and limits their efficacy. We have previously shown that the...
Acquired resistance during BRAF inhibitor therapy remains a major challenge for melanoma treatment. Accordingly, we evaluated the phenotypical and molecular changes of isogeneic human V600E BRAF-mutant melanoma cell line pairs pre- and post-treatment...
Cutaneous melanoma is the deadliest skin cancer. Most have Ras-MAPK pathway (BRAFV600E or NRAS) mutations and highly effective targeted therapies exist; however, they and immune therapies are limited by resistance, in part driven by small GTPase (Rho...
The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resis...
B-RAF is a serine/threonine kinase that plays a crucial role in the MAPK signaling pathway, regulating cell proliferation and survival. Mutations in B-RAF, particularly V600E, are associated with several malignancies, including melanoma, colorectal c...
Background/Objectives: Drug resistance poses a substantial clinical challenge in melanoma treatment, yet the underlying mechanism remains elusive. Here, we report the novel role of laminB1, a nuclear structure protein, in regulating the response of B...
Targeted therapies, including treatment with inhibitors of BRAFV600 and MEK kinases, have improved outcomes in advanced melanoma. However, most patients relapse due to acquired resistance, underscoring the need for new drug targets. This study evalua...
Malignant melanoma is significant problem for Caucasian population in the western countries. Mutations in BRAF gene in 60% of patients is responsible for developing resistance to BRAF inhibitors. Our results delineated the mechanism of resistance and...
Melanoma is the deadliest form of skin cancer, primarily due to its high metastatic propensity and therapeutic resistance in advanced stages. The frequent inactivation of the p53 tumour suppressor protein in melanomagenesis may predict promising outc...
Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is alter...
Metastatic melanoma accounts for the highest number of skin cancer-related deaths. Traditional treatments are ineffective due to their inability to induce tumor regression at a high rate. Newer treatments such as immune checkpoint inhibitors (ICI), t...
Telmisartan, an angiotensin II type 1 receptor (AT1R) antagonist, possesses cytotoxic activity towards BRAF-mutated melanoma cell lines. However, its antihypertensive effects limit its use in the population of normotensive patients. To mitigate this...
Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpre...
BRAFV600 mutations in melanoma are targeted with mutation-specific BRAF inhibitors in combination with MEK inhibitors, which have significantly increased overall survival, but eventually lead to resistance in most cases. Additionally, targeted therap...
Melanoma tumors exhibit a wide range of heterogeneity in genomics even with shared mutations in the MAPK pathway, including BRAF mutations. Consistently, adaptive drug resistance to BRAF inhibitors and/or BRAF plus MEK inhibitors also exhibits a wide...
Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise,...
Background: Metastatic melanoma is a highly aggressive malignancy with poor prognoses and frequent resistance to conventional chemotherapy. Approximately 40% of melanoma cases carry the BRAFV600E mutation, for which vemurafenib, a selective BRAFV600E...
High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species...
Vemurafenib is a BRAF (rapidly accelerated fibrosarcoma B-type)-targeted therapy used to treat patients with advanced, unresectable melanoma. It inhibits the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway...
The incorporation of individualized molecular therapeutics into routine clinical practice for both non-small cell lung cancer (NSCLC) and melanoma are amongst the most significant advances of the last decades in medical oncology. In NSCLC activating...
(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytost...
Nearly half of patients with advanced and metastatic melanomas harbor a BRAF mutation. Vemurafenib (VEM), a BRAF inhibitor, is used to treat such patients, however, responses to VEM are very short-lived due to intrinsic, adaptive and/or acquired resi...
BRAF mutations are present in 30–50% of cases of cutaneous melanoma, and treatment with selective BRAF and MEK inhibitors has been introduced. However, the development of resistance to these drugs often occurs. Chemo-resistant melanoma cells sh...
(1) Malignant melanomas are dangerous skin cancers, and the treatment of melanomas with various cytostatic drugs often causes side effects and after their prolonged use resistance to these drugs appears. The aim of this study was to evaluate the anti...
The discovery of the BRAFV600E mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the developmen...
Whereas the prevalence of several cancer types is decreasing, skin malignancies are growing more common every year. Malignant melanoma is the most aggressive form of skin cancer with high metastatic capacity. In most cases, malignant melanoma shows a...
Melanoma is an aggressive form of skin cancer marked by unique genetic alterations that promote tumor growth and resistance to therapy. Advances in targeted therapy have markedly improved clinical outcomes by selectively inhibiting key oncogenic path...
Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms...
A vast majority of BRAF V600E mutated melanoma patients will develop resistance to combined BRAF/MEK inhibition after initial clinical response. Resistance to targeted therapy is described to be accompanied by specific metabolic changes in melanoma....
BRAF-targeted therapies are widely used for the treatment of melanoma patients with BRAF V600 mutations. Vemurafenib, dabrafenib as well as encorafenib have demonstrated substantial therapeutic activity; however, as is the case with other chemotherap...
Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In additi...
Melanoma is considered a lethal and treatment-resistant skin cancer with a high risk of recurrence, making it a major clinical challenge. Our earlier studies documented that 1,25(OH)2D3 and its low-calcaemic analogues potentiate the effectiveness of...
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