NRAS Q61

This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.

However, parity decreased the overall prevalence of tumors bearing Krasmut, and the magnitude of this decrease depended on both the number and timing of pregnancies. These multistage models may be useful for elucidating biological features of premalignant mammary neoplasia.

Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.

Tumour thickness ≥ 4 mm, ulceration, the coexistence of regression and TILs, and positive BRAFV600E were risk factors for poor prognosis of CoM patients. Besides, expression level of BRAFV600E was positively correlated with the expression levels of PD-1 and PD-L1.

Therefore, the seven SNPs were identified as high-risk SNPs. Conclusions Given that SNPs have the potential to be candidates for cellular alterations brought on by mutations that are associated with cancer, this study provides vital information about how SNPs might be utilized as a diagnostic marker for cancer.

The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.

Patients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA.

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2024 --> Jan 2025

A subset (10.3%) of multifocal PTCs had discordant molecular drivers and 90.0% of them were a combination of BRAF-positive and kinase gene fusion-associated PTCs, mostly with different histologic subtypes. Half of the cases had nodal metastasis and 40% (2/5) of them showed simultaneous involvement by tumors with discordant molecular drivers. These findings highlight the clinical importance of identifying such cases given the potentially different management with specific targeted therapies.

Additionally, CT2A-luc demonstrated substantial baseline secretion of the CCL-2, CCL-5, and CCL-22 chemokines, which play important roles as myeloid chemoattractants. Although the clinical contexts that can be modeled by GL261 and CT2A for huGBM are limited, CT2A may be an informative model of immunotherapy resistance due to its deficits in antigen presentation machinery and interferon response pathways.

CNS melanomas based on NCM in childhood are aggressive malignancies without curative treatment to date. Therapeutic approaches must be individualized. Genetic tumor sequencing is essential to improve understanding of tumorigenesis and potentially identify new therapeutic targets.

P1, N=120, Recruiting, InxMed (Shanghai) Co., Ltd. | Trial completion date: Jun 2024 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

Demographic details, tumor characteristics, and 10-year outcome data were also obtained.Ten cases with BRAF V600E mutations (11.6%) and five (5.49%) NRAS mutations (4 at Q61R, 1 at Q61K) were detected. No statistically significant differences were noted between groups for age, gender, depth of invasion, nodal status, or recurrence status (p ≥ 0.05).These findings suggest that the Irish population has a markedly lower incidence of BRAF and NRAS mutations in melanoma than those reported in other cohorts.

No recurrence or carcinoma development was observed in any of the IUP cases during the follow-up period. Thus, we confirmed the importance of RAS pathway activation in IUP pathogenesis, an association between RAS family gene mutations and IUP subtypes, and the spread patterns of IUP cells within the surface.

A significant ex vivo inhibition of proliferation with the combination of roflumilast+cobimetinib was observed compared to dimethyl sulfoxyde control in both models (51 and 67%). To decipher molecular mechanisms underlying this effect, we performed transcriptomic analyses and revealed a decrease in MKI67, RAF1 and CCND1 expression under bitherapy. Our findings strengthen the therapeutic interest of PDE4 inhibitors and support further experiments to evaluate this approach in metastatic melanoma.

Conclusion  This constitutes one of the few reports on comprehensive analysis of molecular alterations underlying melanomas in Indian patients. A larger sample size, with more extensive molecular markers, would yield additional information on the disease manifestation.

Finally, we predict binding and provide structural models of NRAS antigens spanning the entire HLA allelic landscape, together with in vitro validation for HLA-A*01:191, HLA-B*15:01, and HLA-C*08:02. Our work provides a basis to delineate the solution surface features and immunogenicity of clinically relevant neoepitope/HLA targets for cancer therapy.

In our Brazilian cohort of mCRC patients, frequencies of RAS and BRAF mutations were similar to worldwide data. However, we found lower than expected frequency of MSI-high tumors. KRAS G12C mutation was associated with early-onset mCRC, an emergent population in which KRAS G12C inhibitors might be particulary useful.

PTPN11 and NRAS were the most frequent mutations and RTK-RAS signaling pathway was the most involved pathway in rare AML patients with t(16; 21)(p11; q22)/ FUS: : ERG. The addition of signaling pathway inhibitors followed by HSCT might be an effective strategy to overcome the dismal outcome of this subtype. Larger cohort studies are warranted to investigate the molecular characteristics further as well as evaluate the clinical activity of the SHP2 (PTPN11) inhibitors in FUS: : ERG AML patients.

Twenty tested cases showed retained SMARCA4 expression. We conclude that ATCs express a number of divergent lineage markers that can cause diagnostic dilemmas, as they are also features of other tumors in the differential diagnosis of high-grade midline neck malignancies.

These findings suggest convergent genomic evolution in the MAPK pathway may be a potential mechanism of acquired resistance to FGFRi.

In addition to well-characterized MM drivers (KRAS, NRAS, etc.), 16 new candidate genes were found significantly mutated, including IKFZ3 (Aiolos), a transcription factor and direct target of degradation with lenalidomide therapy, harboring frameshift and stop-gain mutations in the protein dimerization domain which could affect complete differentiation of plasma cells...Conclusion These results highlight the power of genomic profiling in MM for early detection, discovery of novel drivers, monitoring of clonal selection and transformation to malignant disease. We show SMM is not a simple genomically-mature disorder, but rather a dynamic state with competing subclones, which could be leveraged for therapeutic interventions.

RMC-7977 is a potent, oral small molecule inhibitor of both wild-type and mutant GTP-bound RAS oncoproteins (RASMULTI) and is a preclinical tool compound representative of the clinical candidate RMC-6236, currently in clinical evaluation (NCT05379985)...Gilteritinib and the gilteritinib/venetoclax combination selected for survival of cells harboring NRAS mutations, but RMC-7977 inhibited outgrowth of all cell populations...In vivo studies investigating the tolerability and activity of RMC-7977 and RMC-7977 combinations in RAS mutant/FLT3i-resistant patient-derived xenograft models are ongoing and will be presented. Collectively, our data provide preclinical evidence that combination therapies leveraging RASMULTI(ON) inhibition are effective in suppressing RAS-mutant AML clones, a common mechanism of resistance to currently approved targeted therapies in AML and a current area of high unmet clinical need.

MDC-MMAE was pre-clinically evaluated both in-vitro and in-vivo, in human MM cell lines, patient cells and a doxycycline inducible mutant KRAS cell system...It can also be combined with other MM standard of care drugs and with immunotherapy drugs to have a potentially important clinical effect. In collaboration with Tezcat Biosciences, the MDC-MMAE technology has achieved a phase II SBIR for advancement to clinical application.

Primary limitations include the total quantity of single cells and breadth of available genomic subtypes plus inherent noisiness of the applied methodologies. Nonetheless, these findings nominate novel, testable therapeutic targets.

Compared to LDH and S100B, ctDNA levels in stage I to III MM display superior sensitivity to detect MRD and could complement regular FU in predicting tumor progression. In the currently initiated prospective study part (MeLB), we will evaluate ctDNA as marker for MRD identifying patients with stage IIB to III MM at risk for relapse. We will include 50 patients followed for two years quarterly and compare standard singleplex with novel multiplex ddPCR strategies (parallel detection of up to 10 ctDNA mutations) and a custom design NGS panel.

We induced mice with 4-OH tamoxifen ± UV exposure to accelerate melanoma development...Our model allows studies of PDL1 signals in melanomagenesis and progression and distinguishes bona fide tumor cell-intrinsic PDL1 signals and influences on the TME. Conclusions Our novel model distinguishes bona-fide cell-intrinsic PDL1 signals from potential genetic PDL1KO compensation confounding effects, allows studies of earliest PDL1 signals in melanomagenesis and progression, helps understand if PDL1 affects NRAS-driven oncogenesis, and helps test immunotherapy and small molecule treatment effects.

 A biopsy of a newly developed metastasis from the trunk showed an identical biphenotypic pattern and had a common mutational pattern with the same NRAS Q61K mutation and loss of CDKN2A.  The patient also developed metastases to the lung, thyroid, pancreas, axillary lymph nodes, liver, and kidney.  A biphenotypic epithelioid and spindle pattern of melanocytic tumors has been well reported in primary melanomas but our case is unique in that multiple metastases shared this distinct pattern.  In this report, we raise awareness that cutaneous metastases may also show a distinct biphenotypic patten with a nodular and desmoplastic melanoma component.  Our case is unique, showing multiple metastases with this same pattern.  Poster type: Poster Defense

Even focal expression of a melanocytic marker should cast doubt on a diagnosis of PDS and raise the possibility of de-differentiated melanoma, since therapy and outcomes are significantly different. Poster type: Poster Defense

Pulmonary thyroid tissue is uncommon. The presence of this should raise suspicion for thyroid cancer.

These findings argue against the development of 'early' resistance mechanisms after neratinib and pemetrexed exposure. Future studies will be required to understand how NSCLC cells become resistant to neratinib and pemetrexed.

UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future.

P1/2, N=39, Completed, Gritstone bio, Inc. | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Mar 2023 | Trial primary completion date: Dec 2023 --> Mar 2023

Unlike AID-Cre+/-mice, AIDCreERT2 +/- mice express Cre recombinase under the control of an AID promoter and tamoxifen. Mice carrying a combination of these traits developed clonal expansion of clonal CD138+ MM cells in the bone marrow and experienced MGUS and MM as they aged (100% of mice after 6 months of age)... Our newly generated third generation AEY-PK/V/QM mice with short latency and high penetrance are feasible for preclinical studies without the need of transplantation avoided potential Graft vs. Host Disease (GVHD) from different mice.

The MAPK DM, high TMB and persistent genomic instability suggest roles for MAPK-targeted therapies, immunotherapies and DNA damage repair pathway inhibitors, respectively, in EMD. Recurrent codon 61 mutations in RAS suggest a specific role in EMD progression.

Subsequent selection via transplantation and bortezomib (Btz) treatment established transplantable t-Vk*MYC lines (e.g. t-Vk12653) that shows reduced response to Btz in vivo...Compared to Group A VQ and t-Vk12653 MM models, Group B VQ expresses additional hrMM and ultra hrMM features, including downregulation of Fam46c, expression of UAMS-70 and EMC-92 hrMM gene signatures and Amp1q-associated PBX1-FOXM1 gene signatures, upregulation of cancer growth pathways associated with functional hrMM, and de novo resistance to venetoclax in vitro and to Btz and anti-TIGIT immune checkpoint blockade in vivo... Our study provides a strong rational to develop Tra-based immunotherapies for treating RAS-driven hrMM and ultra hrMM.

Each OSUMMER cell line possesses distinct in vitro growth properties, trametinib sensitivity, mutational signatures, and predicted antigenicity. Analysis of OSUMMER allografts shows a correlation between strong, predicted antigenicity and poor tumor outgrowth. These data suggest that the OSUMMER lines will be a valuable tool for modeling the heterogeneous responses of human melanomas to targeted and immune-based therapies.

Additionally we observed BRAF PCMs more commonly originated from naevi. These distinct clinicopathological characteristics may be associated with more aggressive tumour behaviour and as such can assist management decisions taken at multidisciplinary team meetings.