LC-ESI-MS/MS method validation for simultaneous quantification of FDA-approved anticancer agents futibatinib and binimetinib in rat plasma: Insights from preclinical pharmacokinetics.

This study investigates the combination of FGFR inhibitor futibatinib (FTB) and MEK inhibitor binimetinib (BTB) for KRASmt NSCLC therapy. An analytical method was developed and validated for measuring FTB and BTB concentrations in rat plasma, adhering to USFDA guidelines. Using liquid-liquid extraction on 45-µL plasma samples, a 6.5-min run time was achieved. The linear calibration curve ranged from 2 to 100 ng/mL. Intra-day and inter-day accuracy ranged between 92.06% and 100.08%. Four blank injections post high-concentration samples resolved significant carryover. Extraction recoveries averaged 92.06% to 102.37% across concentrations. No significant endogenous interference was detected in blank plasma. The LLOQ for both drugs was 2.0 ng/mL. Selectivity, matrix effects, stability, and dilution integrity met the acceptance criteria. The method assessed FTB and BTB interaction potential in combination therapy at 5 mg/kg. The findings provide essential pharmacokinetics insights for future clinical trials.

LncRNA HOXB-AS3 promotes proliferation, migration, and invasion of gallbladder cancer cells by activating the MEK/ERK pathway.

Background: LncRNA HOXB-AS3 are associated with tumor progression in several types of carcinomas, yet, its possibly biological role in gallbladder carcinoma(GBC) remains unclear. Therefore, this study aimed to investigate the biological function of HOXB-AS3 in GBC. Methods: To know the potential function of HOXB-AS3 in gallbladder carcinoma, real-time polymerase chain reaction was used to detected the expression of HOXB-AS3 in gallbladder carcinoma cells. The colony formation assay and cell counting kit-8 assay was performed to measured cell viability. Flow cytometry was to analyse cell apoptosis and cell cycle. Cell invasion and migration were determined by the transwell invasion assay and wound-healing assay. A nude mice xenograft tumor model was performed to investigate the biological function of HOXB-AS3 in vivo. Results: The results indicated that HOXB-AS3 was significantly elevated in gallbladder carcinoma tissues and cell lines. We used siHOXB-AS3 to knockdown the expression levels of HOXB-AS3. And knockdown HOXB-AS3 expression depressed gallbladder cancer cell viability and induced cell apoptosis. In addition, the gallbladder carcinoma cell cycle was obviously arrested at the G1 phase. Cell invasion and migration were markedly suppressed following knockdown HOXB-AS3 expression. Furthermore, the features of siHOXB-AS3 in gallbladder cancer cells could be reversed by the ERK1/2 phosphorylation agonist Ro 67-7476. Finally, we confirmed that HOXB-AS3 promoted the growth of transplanted tumors in vivo. Conclusion: HOXB-AS3 promoted gallbladder carcinoma cell proliferation, invasion and migration by activating the MEK/ERK signaling pathway. HOXB-AS3 contributed to gallbladder cancer tumorigenesis and metastasis, making it a viable therapeutic target for gallbladder cancer treatment.

Efficacy of trametinib in a metastatic urothelial carcinoma patient with a BRAF mutation.

Introduction: BRAF mutations in bladder cancer are rare. MEK inhibitors have excellent clinical benefits in the treatment of melanoma. Case presentation: A 60-year-old male was diagnosed with muscle-invasive bladder cancer and underwent total cystectomy and ileal conduit diversion. Despite 4 cycles of gemcitabine and cisplatin chemotherapy and 3 courses of pembrolizumab, the left obturator lymph node enlarged. Cancer multi-gene panel testing confirmed the BRAF G469A mutation and trametinib was recommended. Three months after the initiation of trametinib (2 mg, qd), the left obturator lymph node shrank by more than 50%. The disease has remained stable for more than 18 months. Conclusion: The present case indicates the potential of trametinib to treat mBUC patients with the BRAF G469A mutation in this setting.

Case report: Metastatic BRAF V600E-mutated adult Wilms' tumor with robust response to BRAF/MEK inhibitor therapy.

Nephroblastoma or Wilms' tumor (WT) is the most common pediatric renal malignancy but rare in adults. Treatment protocols for adults are typically extrapolated from pediatric guidelines, but there are no standard guidelines for adults due to the rarity of the disease. However, next-generation sequencing has led to new therapeutic options for adult WT patients. We present the first case to our knowledge of a recurrent adult WT treated with dual BRAF/MEK-targeted therapy, which showed initial robust clinical response and was well tolerated.

CircRAPGEF5 acts as a modulator of RAS/RAF/MEK/ERK signaling during colorectal carcinogenesis.

Mutations in oncogenes such as KRAS, NRAS and BRAF promote the growth and survival of tumors, while excessive RAS/RAF/MEK/ERK activation inhibits tumor growth. In this study we examined the precise regulatory machinery that maintains a moderate RAS/RAF/MEK/ERK pathway activation during CRC. Here, using bioinformatic analysis, transcriptomic profiling, gene silencing and cellular assays we discovered that a circular RNA, circRAPGEF5, is significantly upregulated in KRAS mutant colorectal cancer (CRC) cells. CircRAPGEF5 suppressed mutant and constitutively activated KRAS and the expression of the death receptor TNFRSF10A. Silencing of circRAPGEF5-induced RAS/RAF/MEK/ERK signaling hyperactivation and apoptosis in CRC cells suggesting that an upregulation of circRAPEF5 may suppress the expression of TNFRSF10A and aid CRC progression by preventing apoptosis, while the direct interactions between circRAPGEF5 and elements of the RAS/RAF/MEK/ERK pathway was not identified, which nevertheless can be the basis for future research. Moreover, EIF4A3, was observed to share a similar expression pattern with circRAPEF5 and demonstrated to be a major controller of circRAPGEF5 via the promotion of circRAPGEF5 circularization and its silencing reduced circRAPGEF5 levels. Taken together, our findings reveal a mechanism of accurate RAS/RAF/MEK/ERK signaling regulation during CRC progression maintained by upregulation of circRAPGEF5 which may be a plausible target for future clinical applications that seek to induce CRC cell apoptosis via the RAS/RAF/MEK/ERK signaling pathway.

Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer.

BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts. METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage. RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts. CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

SARS-CoV-2 NSP14 induces AP-1 transcriptional activity via its interaction with MEK.

The NSP14 protein of SARS-CoV-2 not only facilitates viral replication but also plays a pivotal role in activating the host immune system by enhancing cytokine production. In this study, we found that NSP14 markedly activated the activator protein 1 (AP-1) pathway by increasing the phosphorylation of ERK (p-ERK), which enters the nucleus and promotes AP-1 transcription. The screening of the main proteins of the ERK pathway revealed that NSP14 could interact with MEK, a kinase of ERK, and increase the level of phosphorylated MEK. The addition of the MEK inhibitor U0126 suppressed the level of p-ERK induced by NSP14 and partly blocked cytokine production, suggesting that NSP14 activates MEK to enhance AP-1 signaling. Further investigation demonstrated that the ExoN domain of NSP14 might be crucial for the interaction and activation of MEK. These results suggest a novel mechanism by which NSP14 of SARS-CoV-2 induces a proinflammatory response in the host.

Mucocutaneous toxicities from MEK inhibitors: a scoping review of the literature.

BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.

Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer.

Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

Inhibition of AIM2 expression enhance treatment effect of osimertinib in treatment of glioma.

INTRODUCTION: Glioma is one of the most commonly tumours which occurs in the central nervous system and accounts for nearly 80% of brain tumours, with a significantly high mortality and morbidity. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as EGFR targeted therapy in various types of solid tumours; however, effective treatment for glioma is still limited. Osimertinib is an irreversible, oral third-generation TKI that targets the mutation at T790M, which causes cancer cells to acquire resistance to drugs. Osimertinib could be effective in the treatment of EGFR mutations with minimal effects on the activity of wild-type EGFR. Absent in melanoma 2 (AIM2) is highly expressed in glioma cells, promoting the maturation of pro-cancer cytokines and contributing to progression of glioma. However, the secretion of pro-cancer cytokines of tumour cells has been regarded as the resistance mechanism to EGFR-TKIs, including osimertinib. A high level of these cytokines also indicates a shorter progression-free survival (PFS). As AIM2 regulates the secretion of pro-cancer cytokines, we thought inhibition of AIM2 may contribute to the therapeutic effect of EGFR-TKIs. MATERIAL AND METHODS: We first established AIM2 inhibition and overexpression in cells. Then, the viability rate of cells was calculated by cell counting kit-8 (CCK-8) method, and apoptotic ratio of cells were measured by flow cytometry. The expression of inflammatory-related genes was detected using quantitative polymerase chain reaction (qPCR), concentrations of inflammatory-related factors were measured using enzyme-linked immunosorbent assay (ELISA). The expression of Wnt/b-catenin and EGFR/Ras/Mitogen-activated protein kinase kinase 1 (MEK) signalling pathway components was detected using western blotting. RESULTS: We found that inhibition of AIM2 enlarged the effect of osimertinib on the upregulation of inflammatory gene expression and secretion of these genes, increasing apoptosis. In addition, we also found that AIM2 could enhance the effect of osimertinib on reducing the expression of the Wnt/b-catenin and EGFR/Ras/MEK signalling pathways, resulting in the inhibition of cellular proliferation, and exerting an anti-tumour effect. These effects were also observed using in vivo experiments. CONCLUSIONS: AIM2 presents a potential therapeutic target in treatment of glioma.

Advances in the Treatment of Pediatric Low-Grade Gliomas.

PURPOSE OF REVIEW: Pediatric low-grade gliomas (pLGGs) often result in significant long-term morbidities despite high overall survival rates. This review aims to consolidate the current understanding of pLGG biology and molecular features and provide an overview of current and emerging treatment strategies. RECENT FINDINGS: Surgical resection remains a primary treatment modality, supplemented by chemotherapy and radiotherapy in specific cases. However, recent advances have elucidated the molecular underpinnings of pLGGs, revealing key genetic abnormalities such as BRAF fusions and mutations and the involvement of the RAS/MAPK and mTOR pathways. Novel targeted therapies, including MEK, BRAF and pan-RAF inhibitors, have shown promise in clinical trials, demonstrating significant efficacy and manageable toxicity. Understanding of pLGGs has significantly improved, leading to more personalized treatment approaches. Targeted therapies have emerged as effective alternatives, potentially reducing long-term toxicities. Future research should focus on optimizing therapy sequences, understanding long-term impacts, and ensuring global accessibility to advanced treatments.

The Investigation of Hsp90 C-terminal inhibitors containing Amide bioisosteres.

Heat Shock Protein 90 (Hsp90) is responsible for the proper folding and maturation of ~400 client protein substrates, many of which are directly associated with the ten hallmarks of cancer. Hsp90 is a great target for cancer therapy including melanoma, since Hsp90 inhibition can disrupt multiple oncogenic pathways simultaneously. In this study, we report the synthesis and anti-proliferative activity manifested by a series of Hsp90 C-terminal inhibitors against mutant BRAF and wild-type BRAF melanoma cells. Furthermore, we explored structure-activity relationships (SAR) for the amide moiety of 6 (B1), a novel Hsp90 C-terminal inhibitor via introduction of amide bioisosteres. Compound 6 displayed an IC50 of 1.01 µM, 0.782 µM, 0.607 µM and 1.413 µM against SKMel173, SKMel103, SKMel19 and A375 cells, respectively.

BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

IL-1ß-activated PI3K/AKT and MEK/ERK pathways coordinately promote induction of partial epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a cellular process in embryonic development, wound healing, organ fibrosis, and cancer metastasis. Previously, we and others have reported that proinflammatory cytokine interleukin-1ß (IL-1ß) induces EMT. However, the exact mechanisms, especially the signal transduction pathways, underlying IL-1ß-mediated EMT are not yet completely understood. Here, we found that IL-1ß stimulation leads to the partial EMT-like phenotype in human lung epithelial A549 cells, including the gain of mesenchymal marker (vimentin) and high migratory potential, without the complete loss of epithelial marker (E-cadherin). IL-1ß-mediated partial EMT induction was repressed by PI3K inhibitor LY294002, indicating that the PI3K/AKT pathway plays a significant role in the induction. In addition, ERK1/2 inhibitor FR180204 markedly inhibited the IL-1ß-mediated partial EMT induction, demonstrating that the MEK/ERK pathway was also involved in the induction. Furthermore, we found that the activation of the PI3K/AKT and MEK/ERK pathways occurred downstream of the epidermal growth factor receptor (EGFR) pathway and the IL-1 receptor (IL-1R) pathway, respectively. Our findings suggest that the PI3K/AKT and MEK/ERK pathways coordinately promote the IL-1ß-mediated partial EMT induction. The inhibition of not one but both pathways is expected yield clinical benefits by preventing partial EMT-related disorders such as organ fibrosis and cancer metastasis.

Hydrolyzed conchiolin protein inhibits melanogenesis through PKA/CREB and MEK/ERK signalling pathways.

OBJECTIVE: Hydrolyzed conchiolin protein (HCP) derived from pearl and nacre extracts exerts skin-lightening effects; however, the underlying molecular mechanisms are not fully understood. Herein, we investigated the effect of HCP on melanogenesis and the signalling pathways involved. METHODS: B16F10 cells and PIG cells were treated with HCP to verify its ability to inhibit melanin. Western Blot, immunofluorescence, and flow cytometry methods were performed to investigate the effect of HCP on melanogenesis signalling pathway proteins. The inhibitors were used to further validate the effect of HCP on PKA/CREB and MEK/ERK signalling pathways. To further evaluate the whitening ability of HCP, changes in melanin were detected using 3D melanin skin model and zebrafish model. RESULTS: HCP was found to significantly inhibit melanin synthesis and decrease the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-2, in a dose-dependent manner. Additionally, we revealed that HCP suppresses melanogenesis via the regulation of the PKA/cAMP response element-binding (CREB) and MEK/extracellular signalling-regulated kinase (ERK) signalling pathways. Using 3D melanin skin models, we demonstrated that HCP can achieve skin-lightening effects by improving apparent chroma, increasing apparent brightness, and inhibiting melanin synthesis. Furthermore, HCP exhibits skin-whitening effects in a zebrafish model. CONCLUSION: These results suggest that HCP suppresses the melanogenesis signalling cascade by inhibiting the PKA/CREB, MEK/ERK signalling pathway and downregulating MITF and its downstream signalling pathways, resulting in decreased melanin synthesis. In summary, HCP is a potential anti-pigmentation agent with promising applications in cosmetics and pharmaceutical products.

OBJECTIF: La protéine conchioline hydrolysée (HCP) dérivée des extraits de perle et de nacre exerce des effets éclaircissants sur la peau ; cependant, les mécanismes moléculaires sous­jacents ne sont pas entièrement compris. Dans cette étude, nous avons investigué l'effet de la HCP sur la mélanogenèse et les voies de signalisation impliquées. MÉTHODES: Les cellules B16F10 et PIG ont été traitées avec la HCP pour vérifier sa capacité à inhiber la mélanine. Des méthodes de Western Blot, d'immunofluorescence et de cytométrie en flux ont été réalisées pour étudier l'effet de la HCP sur les protéines des voies de signalisation de la mélanogenèse. Les inhibiteurs ont été utilisés pour valider davantage l'effet de la HCP sur les voies de signalisation PKA/CREB et MEK/ERK. Pour évaluer plus en détail la capacité éclaircissante de la HCP, les changements de mélanine ont été détectés en utilisant un modèle de peau en 3D de mélanine et un modèle de poisson­zèbre. RÉSULTATS: Il a été constaté que la HCP inhibe significativement la synthèse de la mélanine et diminue l'expression des protéines liées à la mélanogenèse, telles que le facteur de transcription associé à la microphthalmie (MITF), la tyrosinase et la protéine liée à la tyrosinase­2, de manière dose­dépendante. De plus, nous avons révélé que la HCP supprime la mélanogenèse via la régulation des voies de signalisation PKA/cAMP et MEK/ERK. En utilisant des modèles de peau en 3D de mélanine, nous avons démontré que la HCP peut atteindre des effets éclaircissants sur la peau en améliorant la chroma apparente, en augmentant la luminosité apparente et en inhibant la synthèse de la mélanine. En outre, la HCP présente des effets éclaircissants sur la peau dans un modèle de poisson­zèbre. CONCLUSION: Ces résultats suggèrent que la HCP supprime la cascade de signalisation de la mélanogenèse en inhibant les voies de signalisation PKA/CREB et MEK/ERK et en régulant à la baisse le MITF et ses voies de signalisation en aval, ce qui entraîne une diminution de la synthèse de la mélanine. En résumé, la HCP est un agent potentiel anti­pigmentation avec des applications prometteuses dans les produits cosmétiques et pharmaceutiques.

Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

Molecular Susceptibility and Treatment Challenges in Melanoma.

Melanoma is the most aggressive subtype of cancer, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitor resistance in melanoma.

Combination Atezolizumab, Cobimetinib, and Vemurafenib as a Treatment Option in BRAF V600 Mutation-Positive Melanoma: Patient Selection and Perspectives.

The treatment landscape for advanced and metastatic melanoma has drastically changed in recent years, with the advent of novel therapeutic options such as immune checkpoint inhibitors and targeted therapies offering remarkable efficacy and significantly improved patient outcomes compared to traditional approaches. Approximately 50% of melanomas harbor activating BRAF mutations, with over 90% resulting in BRAF V600E. Tumors treated with BRAF inhibitor monotherapy have a high rate of developing resistance within six months. Combination therapy with MEK inhibitors helped to mitigate this treatment resistance and led to improved outcomes. Due to the up-regulation of PD-1/PD-L1 receptors in tumors treated with BRAF/MEK inhibitor therapy, further studies included a third combination agent, anti-PD-1/PD-L1 inhibitors. This triple combination therapy may have superior efficacy and a manageable safety profile when compared with single or double agent therapy regimens.

Effective treatment of advanced and metastatic melanoma can be challenging. Newer treatment methods for patients with BRAF-mutated tumors include a combination of drugs with different complementary mechanisms. These drugs include BRAF-inhibitors, MEK-inhibitors, and PD-1/PD-L1 inhibitors. When these three medications are used in combination, patients may have better response rates and survival outcomes, when compared to using just one or two of these medications together. Toxicity rates are higher with a triple-medication regimen, so careful patient selection is important to consider.

The safety and efficacy of binimetinib for lung cancer: a systematic review.

BACKGROUND: Lung cancer, accounting for a significant proportion of global cancer cases and deaths, poses a considerable health burden. Non-small cell lung cancer (NSCLC) patients have a poor prognosis and limited treatment options due to late-stage diagnosis and drug resistance. Dysregulated of the mitogen-activated protein kinase (MAPK) pathway, which is implicated in NSCLC pathogenesis, underscores the potential of MEK inhibitors such as binimetinib. Despite promising results in other cancers, comprehensive studies evaluating the safety and efficacy of binimetinib in lung cancer are lacking. This systematic review aimed to investigate the safety and efficacy of binimetinib for lung cancer treatment. METHODS: We searched PubMed, Scopus, Web of Science, and Google Scholar until September 2023. Clinical trials evaluating the efficacy or safety of binimetinib for lung cancer treatment were included. Studies were excluded if they included individuals with conditions unrelated to lung cancer, investigated other treatments, or had different types of designs. The quality assessment was conducted utilizing the National Institutes of Health tool. RESULTS: Seven studies with 228 participants overall were included. Four had good quality judgments, and three had fair quality judgments. The majority of patients experienced all-cause adverse events, with diarrhea, fatigue, and nausea being the most commonly reported adverse events of any grade. The objective response rate (ORR) was up to 75%, and the median progression-free survival (PFS) was up to 9.3 months. The disease control rate after 24 weeks varied from 41% to 64%. Overall survival (OS) ranged between 3.0 and 18.8 months. Notably, treatment-related adverse events were observed in more than 50% of patients, including serious adverse events such as colitis, febrile neutropenia, and pulmonary infection. Some adverse events led to dose limitation and drug discontinuation in five studies. Additionally, five studies reported cases of death, mostly due to disease progression. The median duration of treatment ranged from 14.8 weeks to 8.4 months. The most common dosage of binimetinib was 30 mg or 45 mg twice daily, sometimes used in combination with other agents like encorafenib or hydroxychloroquine. CONCLUSIONS: Only a few studies have shown binimetinib to be effective, in terms of improving OS, PFS, and ORR, while most of the studies found nonsignificant efficacy with increased toxicity for binimetinib compared with traditional chemotherapy in patients with lung cancer. Further large-scale randomized controlled trials are recommended.

Three-Year Analysis of Adjuvant Therapy in Postoperative Melanoma including Acral and Mucosal Subtypes.

BACKGROUND: Adjuvant therapy has improved the clinical prognosis for postoperative melanoma patients. However, the long-term efficacy of this therapy on the melanoma acral and mucosal subtypes has not been fully evaluated in previous trials. This study assessed the 3-year recurrence-free survival and overall survival of patients with melanoma, including the acral and mucosal subtypes, treated with anti-PD-1 antibody (Ab) or with the combination of the BRAF and MEK inhibitors dabrafenib and trametinib. METHODS: We retrospectively analyzed both the 3-year time to relapse (TTR) and overall survival (OS) of 120 patients treated with anti-PD-1 antibody (Ab), or with the combination of dabrafenib and trametinib. RESULTS: The overall median TTR was 18.4 months, with a range of 0.69 to 36 months. The 3-year TTR of the acral and mucosal types was 28.1% and 38.5%, respectively. Baseline tumor thickness (TT) and acral type were associated with the TTR in subgroup analysis. Moreover, we classified 104 acral and non-acral cutaneous patients into the anti-PD-1 Abs or dabrafenib plus trametinib combined therapies cohort in multiple analyses. The acral subtype and TT were detected as important prognostic factors. In the 3-year OS, only tumor ulceration was associated with the OS in both univariate and multiple analyses. There was no significant difference in baseline or treatment-related factors of the mucosal type (p > 0.05). CONCLUSION: This study suggests that adjuvant therapy is more effective with non-acral cutaneous melanoma than either the acral or mucosal types at the 3-year TTR endpoint.