NRAS Q61

SAHA imposes a common anti-proliferative core but engages distinct lineage-conditioned risk modules in LUAD and LUSC-cell-cycle/migration-linked in LUAD and checkpoint/stress-linked in LUSC. These SAHA feature-sensing modules provide a mechanistic and clinically anchored framework for subtype-tailored HDAC-directed combinations and for future development of HDACi-aligned biomarkers in NSCLC.

Finally, in an activating NRAS-mutant (p.Q61R) HG-ESS xenograft, the combination of MEK and FAK inhibition dramatically suppressed tumor growth and prolonged survival, highlighting a promising targeted treatment strategy. Overall, our comprehensive analysis defines the molecular basis of ESS and provides a strong preclinical rationale for precision therapies in this aggressive cancer.

Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes.

Together, these results highlight distinct tumorigenic mechanisms in HIV+ DLBCL and underscore the need for mutational profiling of HIV+ DLBCL cohorts worldwide to identify biomarkers and therapeutic targets.

RRASQ87L and RRAS2Q72L are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of RRAS/RRAS2 into routine molecular diagnostic panels for precision oncology and provides preclinical rationale for investigating the potential therapeutic utility of pan-RAS inhibitors for patients with RRASQ87L/RRAS2Q72L-mutant lung cancers.

P1, N=51, Completed, InxMed (Shanghai) Co., Ltd. | Active, not recruiting --> Completed | N=120 --> 51

Melanoma-private mutations in genes such as ARID1A, ARID2, PIK3CA, and CDKN2A indicated additional late events contributing to malignant progression. Overall, this study supports a model in which many melanomas evolve from pre-existing nevi through sequential acquisition and clonal amplification of somatic mutations, while also revealing heterogeneous evolutionary trajectories.

An inactivating ASXL1 variant and an in-frame KDM5B::LPGAT1 fusion were identified in one melanoma; paternal disomy of 11p15.5 in both embryonal rhabdomyosarcomas. Mesenchymal tumors and melanomas showed distinct transcriptional profiles enriched in muscle and synapse organization and epidermal differentiation genes, respectively.

ACE2 negatively showed an inverse correlation with CD8+ T-cell infiltration (r = -0.186, P < 0.001) and PD-L1 expression (r = -0.282, P = 0.022). The upregulation of ACE2 is associated with nerve invasion, pathological type, and an immunosuppressive microenvironment with reduced CD8+ T-cell infiltration and PD-L1 expression.

In this case report, we present the clinico-pathological features of a case of ALES in the nasal septum of a 75-year-old lady, with a hitherto unreported NRAS Q61R mutation. Further studies are required to investigate the prevalence and clinical significance of the NRAS Q61R mutation in ALES.

Germline and somatic DICER1 alterations were common to both. This is the first report of an oncogenic alteration in incipient sarcomatous transformation in a PCN and supports the histogenetic association between PCN and ASK.