NRAS Mutations Research Articles

CDK4 gene copy number increase and concurrent genetic changes in acral melanoma of a Chinese cohort

Acral melanoma (AM) is the most common subtype of melanoma in Asian population. Abnormalities in the p16-cyclin D1-CDK4 signalling pathway play a crucial role in the development and progression of AM. However, the alterations of CDK4 gene copy number in AM are underreported. In this study, we investigated CDK4 gene copy number and concurrent molecular changes in a Chinese cohort with AM, in aim of exploring CDK4 gene alterations and its significance in AM. We examined copy number alterations of CDK4 with fluorescence in situ hybridisation (FISH) in 31 patients with AM. Six patients with CDK4 high-level copy number increase were examined by next-generation sequencing to detect concurrent molecular changes. Using FISH, 12 (12/31, 38.7%) cases showed CDK4 copy number increase, with 6 (6/31, 19.4%) low-level copy number increase and 6 (6/31, 19.4%) high-level copy number increase. Five of six CDK4 low-level copy number increase cases were accompanied by polysomy of chromosome 12, while one case was not. Two of six CDK4 high-level copy number increase cases were accompanied by polysomy of chromosome 12, while four cases were not. CDK4 copy number increase was significantly correlated with younger patient age. In six CDK4 high-level copy number increase cases, one case was found to be accompanied by NRAS mutation, one case was accompanied by HER2 mutation, one case was accompanied by BCL2L11 mutation ​and one case was accompanied by BRAF, HER2 and BCL2L11 mutations. Our study confirmed the presence of CDK4 copy number increase in AM cases. Detecting CDK4 copy number increase by FISH can be reliable in the diagnosis of AM. Some CDK4 copy number increases are the results of polysomy of chromosome 12. CDK4 high-level copy number increase coexists with other pathogenic mutations in AM. CDK4 appears to be a promising target for AM treatment and is expected to be combined with other targeted therapies.

1413: Can NRAS mutation status predict outcome in head and neck mucosal melanoma treated with carbon ions?

1413: Can NRAS mutation status predict outcome in head and neck mucosal melanoma treated with carbon ions?

PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes.

Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations. The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA. PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3.7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable. Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers.

Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma.

This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose-response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.

Advances in Melanoma: From Genetic Insights to Therapeutic Innovations.

Advances in melanoma research have unveiled critical insights into its genetic and molecular landscape, leading to significant therapeutic innovations. This review explores the intricate interplay between genetic alterations, such as mutations in BRAF, NRAS, and KIT, and melanoma pathogenesis. The MAPK and PI3K/Akt/mTOR signaling pathways are highlighted for their roles in tumor growth and resistance mechanisms. Additionally, this review delves into the impact of epigenetic modifications, including DNA methylation and histone changes, on melanoma progression. The tumor microenvironment, characterized by immune cells, stromal cells, and soluble factors, plays a pivotal role in modulating tumor behavior and treatment responses. Emerging technologies like single-cell sequencing, CRISPR-Cas9, and AI-driven diagnostics are transforming melanoma research, offering precise and personalized approaches to treatment. Immunotherapy, particularly immune checkpoint inhibitors and personalized mRNA vaccines, has revolutionized melanoma therapy by enhancing the body's immune response. Despite these advances, resistance mechanisms remain a challenge, underscoring the need for combined therapies and ongoing research to achieve durable therapeutic responses. This comprehensive overview aims to highlight the current state of melanoma research and the transformative impacts of these advancements on clinical practice.

Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine

AbstractThe European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine–treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most patients as adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). Although outcomes with venetoclax-azacitidine improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine. The mutational status of TP53, FLT3 internal tandem duplication (FLT3-ITD), NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% confidence interval (CI), 20.2-32.7]; 12.1 months [95% CI, 7.3-15.2]; and 5.5 months [95% CI, 2.8-7.6], respectively). ELN prognostic classifiers did not provide clinically meaningful risk stratification of OS outcomes in patients treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows the classification of these patients into 3 risk groups with distinct differences in median OS. These trials were registered at www.clinicaltrials.gov as #NCT02993523 and #NCT02203773.

A Retrospective Analysis of the Prognostic Factors and Adverse Events in the Treatment of Mucosal Melanoma in a Single Centre.

Background: Despite the dramatic advances in the management of metastatic cutaneous melanoma, there remains no consensus-based, evidence-based strategy for the management of mucosal melanoma. The rare nature of the disease, its late clinical presentation, and distinct tumour biology all complicate efforts to optimise patient outcomes. Methods: To this end, we carried out a monocentric, retrospective analysis of all patients diagnosed with mucosal melanoma and treated between 2013 and 2021. Both tumour- and patient-specific characteristics were recorded, in addition to immune-related adverse events, in order to provide real-world data on disease progression, treatment efficacy, and the identification of prognostic markers. Results: A total of 20 patients were identified (14 females and 6 males), with a mean age at diagnosis of 65.9 years. The median follow-up was 3.9 years (95% CI 1.4-6.4 years) from the initiation of systemic therapy. The median OS in the entire cohort was 1.9 years (95% CI 0.5-3.3 years). Performance status, sex, body mass index, and the presence of brain metastases were not associated with poorer outcomes. However, serum lactate dehydrogenase levels (LDH) (p = 0.04) and an NRAS mutation were markers of a poor prognosis (p = 0.004). Conclusuion: There is a pressing need for real-world, prospective, and clinical trial data to inform the optimal management of mucosal melanoma, and data supporting the use of adjuvant and neo-adjuvant immunotherapy are currently lacking. However, an elevated LDH is a reliable, independent negative prognostic marker. Inter-disciplinary management remains essential in order to develop optimal treatment strategies.

Prognostic impact of codon-specific KRAS mutational status on survival in patients with metastatic colorectal cancer treated with TAS-102 or regorafenib.

75 Background: Previous study demonstrated KRAS (Kirsten rat sarcoma virus) codon G12 mutation as a potential biomarker of resistance in metastatic colorectal cancer (mCRC). Our study aimed to evaluate the prognostic impact of codon-specific KRAS mutational status on survival in patients with mCRC treated with TAS-102 or regorafenib. Methods: mCRC Patients treated with TAS-102 or regorafenib were retrospectively enrolled into our study. Patients were classified into KRAS G12 (KRASG12) mutation and no KRASG12 mutation according to extended RAS testing. Survival was estimated for comparison, stratified by KRAS mutational status and treatment. Kaplan-Meier curves were estimated for overall survival (OS). Results: A total of 183 patients were enrolled into our study, with 91 patients treated with TAS-102 and 92 patients treated with regorafenib. The median age was 63 years old in our cohort. Most patients were male (54%) with left side colon (85%). After extended RAS/RAF mutational testing, 28% patients had KRASG12 mutation, 50% had RAS/RAFWT, 9% had KRASG13 mutation, 8% had KRASother mutation, 3% had NRAS mutation and 2% had BRAF mutation. For patients treated with TAS-102 group, 20% patients had KRASG12 mutation, while for regorafenib group, 38% patients had KRASG12 mutation. The median OS of TAS-102 was 4.5 versus 11.3 months for KRASG12 mutation and no KRASG12 mutation, respectively (p= 0.013). The median OS of regorafenib was 10.5 versus 6.3 months for KRASG12 mutation and no KRASG12 mutation, respectively (p= 0.183). Furthermore, 34% patients with KRASG12 mutation received TAS-102, while 56% patients without KRASG12 mutation received TAS-102. For patients with KRASG12 mutation, the median OS was 4.5 m versus 10.5 months for TAS-102 and regorafenib group, respectively (p= 0.113). For patients without KRASG12 mutation, the median OS was 11.3m versus 6.3 months for TAS-102 and regorafenib group, respectively (p= 0.047). Conclusions: The prognostic impact of KRASG12 was divergent between mCRC patients treated with TAS-102 and regorafenib. Codon-specific KRAS mutational status should be taken into consideration before treatment.

Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma.

This study explores the potential of preclinical in vitro cell line response data and computational modeling in identifying optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. In a drug combination screen of 43 melanoma cell lines, we identified unique dosage landscapes of panRAF and MEK inhibitors for NRAS vs BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma. Computational modeling and molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated in vivo translatability of in vitro dose-response maps by accurately predicting tumor growth in xenografts. Then, we analyzed pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range.

Melanoma Brain Metastases Patient-Derived Organoids: An In Vitro Platform for Drug Screening.

Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study aimed to establish PDOs from melanoma brain metastases (MBM-PDOs) and to test the feasibility of using them as a model for in vitro targeted-therapy drug testing. Surgical resection samples from eight patients with melanoma brain metastases were used to establish MBM-PDOs. The samples were enzymatically dissociated followed by seeding into low-attachment plates to generate floating organoids. The MBM-PDOs were characterized genetically, histologically, and immunohistologically and compared with the parental tissue. The MBM-PDO cultures were exposed to dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) followed by a cell viability assessment. Seven out of eight cases were successfully cultivated, maintaining the histological, immunohistological phenotype, and the mutational status of the parental tumors. Five out of seven cases harbored BRAF V600E mutations and were responsive to BRAF and MEK inhibitors in vitro. Two out of seven cases were BRAF wild type: one case harboring an NRAS mutation and the other harboring a KIT mutation, and both were resistant to BRAF and MEK inhibitor therapy. We successfully established PDOs from melanoma brain metastases surgical specimens, which exhibited a consistent histological and mutational profile with the parental tissue. Using FDA-approved BRAF and MEK inhibitors, our data demonstrate the feasibility of employing MBM-PDOs for targeted-therapy in vitro testing.

Observation and Management of Juvenile Myelomonocytic Leukemia and Noonan Syndrome-Associated Myeloproliferative Disorder: A Real-World Experience.

Juvenile Myelomonocytic Leukemia (JMML) is a rare and clonal hematopoietic disorder of infancy and early childhood with myeloproliferative/myelodysplastic features resulting from germline or somatic mutations in the RAS pathway. Treatment is not uniform, with management varying from observation to stem cell transplant. The aim of our retrospective review is to describe the treatment and outcomes of a cohort of patients with JMML or Noonan Syndrome-associated Myeloproliferative Disorder (NS-MPD) to provide management guidance for this rare and heterogeneous disease. We report on 22 patients with JMML or NS-MPD managed at three institutions in the Texas Medical Center. Of patients with known genetic mutations and cytogenetics, 6 harbored germline mutations, 12 had somatic mutations, and 9 showed cytogenetic abnormalities. Overall, 14/22 patients are alive. Spontaneous clinical remission occurred in one patient with somatic NRAS mutation, as well as two with germline PTPN11 mutations with NS-MPD, and two others with germline PTPN11 mutations and NS-MPD remain under surveillance. Patients with NS-MPD were excluded from treatment analysis as none required chemotherapeutic intervention. All patients (5/5) treated with 5-azacitidine alone and one of the four treated with 6-mercaptopurine monotherapy had a reduction in mutant variant allele frequency. Transformation to acute myeloid leukemia was seen in two patients who both died. Among patients who received transplants, 7/13 are alive, and relapse post-transplant occurred in 3/13 with a median time to relapse of 3.55 months. This report provides insight into therapy responses and long-term outcomes across different genetic subsets of JMML and lends insight into the expected time to spontaneous resolution in patients with NS-MPD with germline PTPN11 mutations.

TLE3 Is a Novel Fusion Partner of JAK2 in Myeloid/Lymphoid Neoplasm With Eosinophilia Responding to JAK2 Inhibition.

Chromosomal rearrangements involving Janus kinase 2 (JAK2) are rare but recurrent findings in lymphoid or myeloid neoplasia. Detection of JAK2 fusion genes is important as patients with aberrantly activated JAK2 may benefit from treatment with tyrosine kinase inhibitors such as ruxolitinib. Here, we report a novel fusion gene between the transcriptional co-repressor-encoding gene transducin-like enhancer of split 3 (TLE3) and JAK2 in a patient initially diagnosed with chronic eosinophilic leukemia with additional mutations in PTPN11 and NRAS. The patient was successfully treated with the JAK2 inhibitor ruxolitinib for 8 months before additional somatic mutations were acquired and the disease progressed into an acute lymphoblastic T-cell leukemia/lymphoma. The present case shows similarities to previously reported cases with PCM1::JAK2 and BCR::JAK2 with regard to disease phenotype and response to ruxolitinib, and importantly, provides an example that also patients harboring other JAK2 fusion genes may benefit from treatment with JAK2 inhibitors.

Clinical Characteristics and Prognostic Relevance of Co-Mutated Genes in Acute Myeloid Leukemia Patients with FLT3 Mutations

To investigate the clinical characteristics and influence of co-mutated gene on acute myeloid leukemia patients (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. A total of 273 FLT3+ AML patients were enrolled, and the co-mutation gene data of the patients were collected to further analyze the prognosis of the patients. FLT3 and other common mutations were quantified by PCR amplification products direct sequencing and second-generation sequencing (NGS). When patients were divided into FLT3- ITD +, FLT3- TKD +, FLT3- ITD ++TKD + and FLT3- ITD -+TKD - group according to the type of FLT3 mutations, it was found that the frequencies of TET2, GATA2, NRAS and ASXL1 mutation were significantly different among the 4 groups (all P < 0.05). When patients were divided into allelic ratio (AR) ≥0.5 and <0.5 group, it was found that the frequencies of FLT3- ITD +, FLT3 -ITD - +TKD -, NPM1, NRAS and C-kit were significantly different between the two groups (all P < 0.05). When patients were divided into normal and abnormal karyotype group, it was found that the frequencies of FLT3- ITD +, FLT3- TKD +, NPM1, GATA2 and C-kit were significantly different between the two groups (all P < 0.05). The median overall survival (OS) of AML patients with FLT3 -TKD + (including FLT3- ITD ++TKD +) was longer than that of patients with FLT3- ITD + alone (P < 0.05). The OS and relapse-free survival (RFS) of AML patients with FLT3++TET2+ were both shorter than those of patients with FLT3++TET2- (both P < 0.05). The mutation frequencies of co-mutated genes are correlated with subtypes of FLT3, karyotype and AR. AML patients with FLT3 -TKD + have longer OS than patients with FLT3- ITD + alone, and patients with co-mutation of TET2 have shorter median OS and RFS.

Genomic profiling of lymph node and distant metastases from papillary and poorly differentiated thyroid carcinomas

PurposeTo perform a molecular profiling of the metastases from papillary thyroid carcinomas (PTCs) and poorly differentiated thyroid carcinomas (PDTCs).MethodsWe retrieved and analyzed the molecular and clinical features of 136 metastases from PTCs and 35 metastases from PDTCs subjected to targeted DNA sequencing, from cBioPortal. The clinicopathological data included the number and location of the metastases, and genomic data included mutations, translocations, copy number alterations and fraction of the genome altered (FGA).ResultsBone metastases from PTCs had a lower frequency of BRAF mutations than the lymph node metastases (LNMs) (43% vs 88%, p < 0.01), and a higher frequency of RBM10 and NRAS mutations than the LNMs (21% vs 3% for both, p < 0.05). The FGA of the bone metastases was higher than the FGA of the lung metastases (5.6% vs 1.3%, p < 0.05). The frequency of RET translocations was higher in the lung metastases from PTCs than the LNMs (15% vs 3%, p < 0.05). The LNMs from PTC patients harboring 4 or more distant metastases (DMs) had a higher frequency of TERT promoter mutations than the LNMs from patients harboring less than 4 DMs (96% vs 65%, p < 0.001). SDHA gene amplifications were enriched in the bone metastases from PDTCs and absent in the LNMs (38% vs 0%, p < 0.05).ConclusionMetastases from PTCs and PDTCs harbor clinically relevant alterations affecting distinct body locations, such as NRAS and RBM10 mutations, RET translocations and SDHA amplifications that may be explored therapeutically.

Comprehensive insights on genetic alterations and immunotherapy prognosis in Chinese melanoma patients

Immune checkpoint inhibitors (ICI) have emerged as a promising therapeutic option for melanoma, which demonstrating improved clinical outcomes in melanoma patients regardless of specific genetic mutations. However, the identification of reliable biomarkers for predicting immunotherapy response and prognosis remains a challenge. In this study, we performed genetic profiling of the melanoma patients with different subtypes and evaluated the efficacy of ICI treatment. A total of 221 melanoma patients were included in our cohort, consisting primarily of acral lentiginous melanoma (ALM), cutaneous malignant melanoma (CMM), and mucosal malignant melanoma (MMM). Genetic analysis revealed BRAF mutations was predominant in CMM and NRAS mutations was prevalent in ALM. Copy number variants (CNVs) and structural variants (SV) were also detected, with CCND1 and CDK4 being the most affected genes in CNV and BRAF, ALK and RAF1 being the druggable targets in SV. Furthermore, NRAS mutations were associated with a poor prognosis in ALM, while TERT mutations were linked to unfavorable outcomes in CMM after receiving PD-1 therapy. Additionally, ALK expression exhibited improved outcomes in both ALM and CMM subtypes. Our study provides a comprehensive genomic and pathological profiling of Chinese melanoma patients, shedding light on the molecular landscape of the disease. Furthermore, numbers of gene mutations and ALK expression were identified as prognostic indicators. These findings contribute to the understanding of melanoma genetics in the Chinese population and have implications for personalized treatment approaches.

Targeting Hyperactive Ras Signaling in Pediatric Cancer.

Somatic RAS mutations are among the most frequent drivers in pediatric and adult cancers. Somatic KRAS, NRAS, and HRAS mutations exhibit distinct tissue-specific predilections. Germline NF1 and RAS mutations in children with neurofibromatosis type 1 and other RASopathy developmental disorders have provided new insights into Ras biology. In many cases, these germline mutations are associated with increased cancer risk. Promising targeted therapeutic strategies for pediatric cancers and neoplasms with NF1 or RAS mutations include inhibition of downstream Ras effector pathways, directly inhibiting the signal output of oncogenic Ras proteins and associated pathway members, and therapeutically targeting Ras posttranslational modifications and intracellular trafficking. Acquired drug resistance to targeted drugs remains a significant challenge but, increasingly, rational drug combination approaches have shown promise in overcoming resistance. Developing predictive preclinical models of childhood cancers for drug testing is a high priority for the field of pediatric oncology.

Primary Meningeal Melanocytic Tumors of the Central Nervous System: A Review from the Ultra-Rare Brain Tumors Task Force of the European Network for Rare Cancers (EURACAN).

Primary meningeal melanocytic tumors are ultra-rare entities with distinct histological and molecular features compared with other melanocytic or pigmented lesions, such as brain and leptomeningeal metastases from metastatic melanoma. The European Network for Rare Cancers (EURACAN) Task Force on Ultra-Rare Brain Tumors (domain 10, subdomain 10) performed a literature review from January 1985 to December 2023 regarding the epidemiologic and clinical characteristics, histological and molecular features, radiological findings, and efficacy of local treatments (surgery and radiotherapy) and systemic treatments for these entities. Molecular analysis can detect specific mutations, including GNAQ, GNA11, SF3B1, EIF1AX, BAP1, that are typically found in circumscribed primary meningeal melanocytic tumors and not in other melanocytic lesions, whereas NRAS and BRAF mutations are typical for diffuse primary meningeal melanocytic tumors. The neuroimaging of the whole neuroaxis suggests a melanocytic nature of a lesion, depicts its circumscribed or diffuse nature, but cannot predict the tumor's aggressiveness. Gross-total resection is the first choice in the case of circumscribed meningeal melanocytoma and melanoma; conversely, meningeal biopsy may be reserved for patients with diffuse and multinodular leptomeningeal spread to achieve a definitive diagnosis. High-dose radiotherapy is rarely indicated in diffuse melanocytic tumors except as palliative treatment to alleviate symptoms. Last, a definitive advantage of a specific systemic treatment could not be concluded, as most of the data available derive from case reports or small cohorts. As primary meningeal melanocytic tumors are extremely rare, the correlations between the clinical characteristics, molecular profile, radiological findings at diagnosis and progression are weak, and poor evidence on the best therapeutic approach is available. There is a need to develop shared platforms and registries to capture more knowledge regarding these ultra-rare entities.

IκBα kinase inhibitor BAY 11-7082 promotes anti-tumor effect in RAS-driven cancers

BackgroundOncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge.MethodsIn this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082.ResultsWe demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition.ConclusionOur study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers.

Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- (“Triple”) wild type melanomas

BackgroundMelanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as “triple wild-type” (tWT) melanomas. They constitute 5–10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. MethodsTargeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. Results184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4–9) and mOS was 24.8 months (95 % CI: 14.2–53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9–8.5) and mOS was 29.18 months (95 % CI: 17.5–46.2). ConclusionsWhile known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors

BackgroundPediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway. MethodsWe utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition. ResultsWe found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis. ConclusionsThe results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.