Search Results (241)

Small molecule inhibitors that target the E3 ligase activity of MDM2-MDM4 have been explored to inhibit the oncogenic activity of MDM2-MDM4 complex. MMRi62 is a small molecule that was identified using an MDM2-MDM4 E3 ligase-based high throughput screen and a cell-death-based secondary screen. Our previous studies showed that MMRi62 promotes MDM4 degradation in cells and induces p53-independent apoptosis in cancer cells. However, MMRi62 activity in solid tumor cells such as melanoma cells, especially in BRAF inhibitor resistant melanoma cells, have not been explored. Although its promotion of MDM4 degradation is clear, the direct MMRi62 targets in cells are unknown. In this report, we show that MMRi62 is a much more potent p53-independent apoptosis inducer than conventional MDM2 inhibitors in melanoma cells. A brief structure-activity study led to development of SC-62-1 with improved activity. SC-62-1 potently inhibits and eliminates clonogenic growth of melanoma cells that acquired resistance to BRAF inhibitors. We developed a pair of active and inactive SC-62-1 probes and profiled the cellular targets of SC-62-1 using a chemical biology approach coupled with IonStar/nano-LC/MS analysis. We found that SC-62-1 covalently binds to more than 15 hundred proteins in cells. Pathways analysis showed that SC-62-1 significantly altered several pathways including carbon metabolism, RNA metabolism, amino acid metabolism, translation and cellular response to stress. This study provides mechanistic insights into the mechanisms of action for MMRi62-like quinolinols. This study also suggests multi-targeting compounds like SC-62-1 might be useful for overcoming resistance to BRAF inhibitors for improved melanoma treatment. Full article

Aldehyde dehydrogenase 2 (ALDH2) is a crucial detoxifying enzyme that eliminates toxic aldehydes. ALDH2 deficiency has been linked to various human diseases, including certain cancers. We have previously reported ALDH2 downregulation in human melanoma tissues. Here, we further investigated the biological significance of ALDH2 downregulation in this malignancy. Analysis of TCGA dataset revealed that low ALDH2 expression correlates with poorer survival in metastatic melanoma. Examination of human metastatic melanoma cell lines confirmed that most had ALDH2 downregulation (ALDH2-low) compared to primary melanocytes. In contrast, a small subset of metastatic melanoma cell lines exhibited normal ALDH2 levels (ALDH2-normal). CRISPR/Cas9-mediated ALDH2 knockout in ALDH2-normal A375 cells promoted tumor growth and MAPK/ERK activation. Given the pivotal role of MAPK/ERK signaling in melanoma and cellular response to acetaldehyde, we compared A375 with ALDH2-low SK-MEL-28 and 1205Lu cells. ALDH2-low cells were intrinsically resistant to BRAF and MEK inhibitors, whereas A375 cells were not. However, A375 cells acquired resistance upon ALDH2 knockout. Furthermore, melanoma cells with acquired resistance to these inhibitors displayed further ALDH2 downregulation. Our findings indicate that ALDH2 downregulation contributes to melanoma progression and therapy resistance in BRAF-mutated human metastatic melanoma cells, highlighting ALDH2 as a potential prognostic marker and therapeutic target in metastatic melanoma. Full article

Background/Objectives: Melanoma is one of the most aggressive forms of skin cancer and is frequently associated with the B-Raf⁶⁰⁰E mutation, which constitutively activates the MAPK signaling pathway. Although selective inhibitors such as Vemurafenib offer clinical benefits, their long-term efficacy is often hindered by resistance mechanisms and adverse effects. In this study, twelve phytochemicals from Brazilian green propolis were evaluated for their potential as selective B-Raf⁶⁰⁰E inhibitors using a computational approach. Methods: Physicochemical, ADME, and electronic properties were assessed, followed by molecular docking using the B-Raf⁶⁰⁰E crystal structure (PDB ID: 3OG7). Redocking validation and 500 ns molecular dynamics simulations were performed to investigate the stability of the ligand-protein complexes, and free energy calculations were then computed. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (−8.17 kcal/mol) in docking and maintained stable interactions with key catalytic residues throughout the simulation, also presenting free energy of binding ΔG of −20.77 kcal/mol. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. Results: Among the tested compounds, Artepillin C exhibited the strongest binding affinity (−8.17 kcal/mol) and maintained stable interactions with key catalytic residues throughout the simulation. HOMO-LUMO and electrostatic potential analyses further supported its reactivity and selectivity. Notably, Artepillin C remained bound within the ATP-binding site, mimicking several critical interactions observed with Vemurafenib. Conclusions: These findings indicate that Artepillin C is a promising natural compound for further development as a selective B-Raf⁶⁰⁰E inhibitor and suggest its potential utility in melanoma treatment strategies. This study reinforces the value of natural products as scaffolds for targeted drug design and supports continued experimental validation. Full article

Targeting the cell cycle has become a focus of cancer research bearing impressive results with the introduction of CDK4/6 inhibitors in the treatment of ER-positive/HER2-negative breast cancers. However, no definitive benefit in other cancers has been observed. In gastrointestinal cancers, despite preclinical studies pinpointing positive effects on cancer inhibition in pre-clinical models, no positive clinical trials have been published with CDK4/6 inhibitors. Several biomarkers have been proposed in breast cancers, where the field is more advanced, and include up-regulations of the inhibited kinases CDK4 and CDK6 and their partner cyclin D as well as the main target of phosphorylation, RB. Up-regulation of Cyclin E, an E2F1/RB regulated gene, also arises as a marker of CDK4/6 inhibition resistance. Signaling from receptor tyrosine kinase pathways through KRAS/BRAF/MEK and PI3K/AKT/mTOR are also implicated in feedback CDK4/6 activation and inhibitors resistance. In gastrointestinal cancers, some of these biomarkers have also proven valuable in predicting sensitivity to CDK4/6 inhibitors and would lead markers to guide clinical development. Modulation of the tumor microenvironment, where immune cells are prominent components, arises as a feature of CDK4/6 inhibition and could be harnessed in therapeutic combinations. Full article

The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, we combined short-term cell viability assays with long-term regrowth assays following drug removal over a period of three weeks. This allowed assessment of regrowth after therapy discontinuation. We tested the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib) on BRAF-V600E mutant CRC patient-derived organoids (PDOs). Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by rapid regrowth after drug removal, mirroring clinical outcomes. EGFR inhibition in BRAF-V600E mutant PDOs led to activation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R). The IGF1R/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented regrowth of CRC PDOs, and improved the anti-tumour response in an in vivo model. PDO regrowth assays allow the identification of pathways driving tumour recurrence. IR/IGF1R-inhibition prevents regrowth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC Full article

Gastrointestinal metastases of malignant melanoma are relatively common and pose significant challenges to clinical management due to their complex presentation and resistance to therapy. Early detection and a multidisciplinary treatment approach are critical to improve outcomes. This review highlights targeted treatment strategies for gastrointestinal melanoma metastases, focusing on current therapeutic options and the mechanisms underlying drug resistance. Advances in immune checkpoint inhibitors (ICIs) and targeted therapies, such as BRAF and MEK inhibitors, have revolutionized melanoma treatment, yet their efficacy is often limited by the emergence of resistance mechanisms, including genetic mutations, tumor microenvironment factors, and immune escape. Herein, we explore potential resistance biomarkers for resistance and emerging targeting treatments targeting these pathways. Understanding the molecular and cellular mechanisms driving drug resistance remains critical to overcoming therapeutic limitations, emphasizing the importance of collaborative efforts in research and clinical practice to refine therapeutic approaches and improve survival rates for patients with metastatic melanoma involving the gastrointestinal tract. Future directions include optimizing combination therapies and leveraging precision medicine to address resistance and disease progression. Full article

Melanoma treatment comprised a few treatment choices with insufficient efficacy before the emergence of molecularly targeted medication and immune checkpoint inhibitors, which dramatically improved patient outcomes. B-Rapidly Accelerated Fibrosarcoma (BRAF) and Mitogen-Activated Protein Kinase (MAPK) Kinase (MEK) inhibitors significantly improved survival in BRAF-mutant melanoma and immune checkpoint inhibitors, such as anti-programmed cell death 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) agents, established new standards of care. Challenges remain, however, including the existence of resistance mechanisms and the reduced efficacy of immune-based therapies in Asian populations, particularly for acral and mucosal subtypes. This review highlights historical and current therapeutic advancements, discusses regional considerations, and explores emerging strategies aiming at globally optimizing melanoma management. Full article

Melanoma, known for its aggressive nature and propensity for developing drug resistance, remains a significant clinical challenge. The emergence of resistance to both targeted therapies (like BRAF/MEK inhibitors) and immunotherapies is a major obstacle to achieving durable responses and improving patient survival. HDACs, a class of epigenetic enzymes, modulate gene expression and chromatin structure by removing acetyl groups from histone and non-histone proteins. In melanoma, aberrant HDAC activity contributes to resistance through multiple mechanisms. HDACs influence key oncogenic signaling pathways frequently dysregulated in melanoma, such as the MAPK, PI3K/AKT, and WNT/β-catenin cascades. By altering the activity of these pathways, HDACs promote the survival and proliferation of melanoma cells even in the presence of therapy. Beyond their direct effects on tumor cells, HDACs also play a crucial role in shaping the tumor microenvironment. They can suppress anti-tumor immune responses by reducing immune cell infiltration, modulating cytokine production, and fostering an immunosuppressive milieu. This further contributes to resistance to immunotherapies. Given the central role of HDACs in these resistance mechanisms, HDAC inhibitors (HDACis) have emerged as potential therapeutic agents to restore drug sensitivity. HDACis can induce cell death, inhibit proliferation, and enhance immune responses in melanoma cells. Preclinical and clinical studies have explored the combination of HDACis with existing therapies to overcome resistance. While promising, the clinical application of HDACis is accompanied by challenges, including toxicity, the need for biomarkers to predict response, and the optimization of combination strategies. Ongoing research is dedicated to developing more selective and potent HDACis and to better understand how to effectively incorporate them into melanoma treatment regimens. This review provides a comprehensive overview of the multifaceted ways in which HDACs contribute to melanoma drug resistance and discusses the potential of HDAC-targeted therapies to improve patient outcomes. Full article

BRAF mutations are critical drivers in cancers such as melanoma, colorectal cancer, and non-small-cell lung cancer. The most common mutation, BRAF V600E, is a key therapeutic target. Targeted treatments with BRAF and MEK inhibitors have significantly improved progression-free and overall survival in melanoma patients. However, in cancers like metastatic colorectal cancer, BRAF mutations are associated with poor outcomes due to aggressive disease behavior and resistance to conventional chemotherapy. Despite progress, resistance to BRAF/MEK inhibitors remains a major challenge, often driven by secondary mutations in the mitogen-activated protein kinase (MAPK) pathway, activation of alternative pathways such as phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), or changes in the tumor microenvironment. These challenges have motivated ongoing research into combining BRAF inhibitors with immunotherapies to enhance and prolong treatment effectiveness. Future research must also account for the role of the cancer’s tissue of origin, as the biological context significantly influences response to targeted therapies, highlighting the need for a deeper understanding of tumor biology, micro-environment, and genetics. Full article

Melanoma is an aggressive cancer with rising incidence, particularly among older individuals. Despite advancements in targeted therapies for BRAF and MEK proteins and immunotherapies, many patients either fail to respond or develop resistance. For those progressing on immunotherapy, limited treatment options remain. The Cyclin D–CDK4/6–RB pathway is commonly dysregulated in melanoma, with up to 90% of cases showing alterations that activate it. Although targeting Cyclin–CDK complexes has shown promise in preclinical models, clinical responses have been suboptimal. This review explores the molecular mechanisms behind Cyclin–CDK dysregulation in melanoma and the challenges of targeting this pathway. It also discusses strategies to improve the efficacy of CDK4/6 inhibitors, including combination therapies to overcome resistance and enhance patient outcomes. Understanding these mechanisms can guide the development of more effective treatments for melanoma. Full article

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 cancer, and non-small cell lung cancer, making it a key therapeutic target. The development of B-RAF inhibitors, such as Vemurafenib, Dabrafenib, and second-generation inhibitors like Encorafenib, has led to significant advancements in targeted cancer therapy. However, acquired resistance, driven by MAPK pathway reactivation, RAF dimerization, and alternative signaling pathways, remains a major challenge. This review explores the molecular mechanisms of B-RAF inhibitors, their therapeutic efficacy, and resistance mechanisms, emphasizing the importance of combination strategies to enhance treatment outcomes. The current standard of care involves B-RAF and MEK inhibitors, with additional therapies such as EGFR inhibitors and immune checkpoint blockades showing potential in overcoming resistance. Emerging pan-RAF and brain-penetrant inhibitors offer new opportunities for treating refractory cancers, while precision medicine approaches, including genomic profiling and liquid biopsies, are shaping the future of B-RAF-targeted therapy. Full article

The poor prognosis for high-grade serous ovarian cancer (HGSOC), the dominant subtype of ovarian cancer, reflects its aggressive nature, late diagnosis, and the highest mortality rate among all gynaecologic cancers. Apart from late diagnosis, the main reason for the poor prognosis and its unsuccessful treatment is primarily the emergence of chemoresistance to carboplatin. Although there is a good response to primary treatment, the disease recurs in 80% of cases, at which point it is largely resistant to carboplatin. The introduction of novel targeted therapies in the second decade of the 21st century has begun to transform the treatment of HGSOC, although their impact on overall survival remains unsatisfactory. Targeting the specific pathways known to be abnormally activated in HGSOC is especially difficult due to the molecular diversity of its subtypes. Moreover, a range of molecular changes are associated with acquired chemoresistance, e.g., reversion of BRCA1 and BRCA2 germline alleles. In this review, we examine the advantages and disadvantages of approved targeted therapies, including bevacizumab, PARP inhibitors (PARPis), and treatments targeting cells with neurotrophic tyrosine receptor kinase (NTRK), B-rapidly accelerated fibrosarcoma (BRAF), and rearranged during transfection (RET) gene alterations, as well as antibody–drug conjugates. Additionally, we explore promising new targets under investigation in ongoing clinical trials, such as immune checkpoint inhibitors, anti-angiogenic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, Wee1 kinase inhibitors, and ataxia telangiectasia and Rad3-related protein (ATR) inhibitors for platinum-resistant disease. Despite the development of new targeted therapies, carboplatin remains the fundamental medicine in HGSOC therapy. The correct choice of treatment strategy for better survival of patients with advanced HGSOC should therefore include a prediction of patients’ risks of developing chemoresistance to platinum-based chemotherapy. Moreover, effective targeted therapy requires the selection of patients who are likely to derive clinical benefit while minimizing potential adverse effects, underscoring the essence of precision medicine. Full article

The treatment landscape of metastatic colorectal cancer (mCRC) has undergone significant evolution, with the introduction of targeted therapies and immunotherapy dramatically altering the management of microsatellite instability-high (MSI-H) tumors. However, the majority of patients, particularly those with microsatellite-stable (MSS) disease, remain refractory to immunotherapy, necessitating the exploration of alternative therapeutic strategies. This review summarizes the current treatment options for heavily pretreated mCRC patients who are not eligible for targeted therapies or clinical trials. Approved therapies for refractory mCRC, including regorafenib, trifluridine/tipiracil (FTD/TPI), and fruquintinib, demonstrate modest survival benefits but are often associated with significant toxicities. Additionally, innovative approaches targeting specific mutations such as KRAS G12C, HER2 amplification, and BRAF V600E are discussed, highlighting emerging combination regimens with immune checkpoint inhibitors and other agents to overcome resistance mechanisms. The potential of rechallenge strategies using previously administered therapies, such as oxaliplatin and anti-EGFR agents, is examined, supported by retrospective and prospective studies. Furthermore, the role of older drugs like mitomycin C in combination with capecitabine is revisited, offering insights into their viability in advanced treatment settings. Ongoing clinical trials with novel agents and combinations are expected to provide further clarity on optimizing sequential treatment regimens and personalizing therapy for mCRC patients. This review emphasizes the need for comprehensive molecular profiling and shared decision-making to improve outcomes and quality of life in this challenging patient population. Full article

The treatment landscape for advanced melanoma has transformed significantly with the advent of BRAF and MEK inhibitors (BRAF/MEKi) targeting BRAFV600 mutations, as well as immune checkpoint inhibitors (ICI) like anti-PD-1 monotherapy or its combinations with anti-CTLA-4 or anti-LAG-3. Despite that, many patients still do not benefit from these treatments at all or develop resistance mechanisms. Therefore, prognostic and predictive biomarkers are needed to identify patients who should switch or escalate their treatment strategies or initiate an intensive follow-up. In melanoma, liquid biopsy has shown promising results, with a potential role in predicting relapse in resected high-risk patients or in disease monitoring during the treatment of advanced disease. Several components in peripheral blood have been analyzed, such as circulating tumor cells (CTCs), cell-free DNA (cfDNA), and circulant tumoral DNA (ctDNA), which have turned out to be particularly promising. To analyze ctDNA in blood, different techniques have proven to be useful, including digital droplet polymerase chain reaction (ddPCR) to detect specific mutations and, more recently, next-generation sequencing (NGS) techniques, which allow analyzing a broader repertoire of the mutation landscape of each patient. In this review, our goal is to update the current understanding of liquid biopsy, focusing on the use of ctDNA as a biological material in the daily clinical management of melanoma patients, in particular those with advanced disease treated with ICI. Full article

Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations. Tumor volumes were quantified using 3D reconstruction of CT scans, and data from Japan’s C-CAT database (n = 2255) provided insights into ctDNA testing in HNSCC. C-CAT data showed that ctDNA testing was underutilized, performed in only 7% of head and neck cancer cases. In SHIZUKU-HN, mean VAF significantly correlated with tumor volume (Spearman’s ρ = 0.70, p = 0.001), often preceding radiographic progression. BRAF and APC mutations disappeared in partial responders, while GNAS mutations varied. EGFR and PIK3CA amplifications, detectable via ctDNA but missed in tissue biopsies, indicated emerging resistance mechanisms. The SHIZUKU-HN study demonstrates the potential of ctDNA as a dynamic biomarker in HNSCC, offering early insights into treatment efficacy and informing personalized ICI therapy. Full article