NRAS Q61

Moreover, FTY720 co-treatment resensitized G12D NRAS-mutated M14(R)701 cells to gilteritinib in vivo. Co-treatment inactivated ERK, transcriptionally downregulated SPHK1, and inactivated downstream AKT, p70 S6K and BAD, with inactivation abrogated by constitutive SPHK1 expression. The clinically applicable S1PR modulators fingolimod and mocravimod resensitize NRAS-mutated FLT3-ITD AML cells to FLT3 inhibitors, supporting potential clinical efficacy.

Pharmacological inhibitors of EZH2, including tazemetostat, have shown promise in preclinical melanoma models by restoring antigen presentation, enhancing CD8+ T-cell infiltration, and reversing transcriptional programs associated with immune resistance. This review aims to summarize the role of EZH2 in the molecular pathogenesis of ALM, emphasizing its contributions to epigenetic regulation, tumor plasticity, and immune escape, and discusses emerging therapeutic strategies targeting EZH2-mediated pathways to improve outcomes for this aggressive melanoma subtype.

P3, N=590, Recruiting, Revolution Medicines, Inc. | N=420 --> 590

Compared to ddPCR and next-generation sequencing, DHCC substantially reduces turnaround time and cost while operating on standard qPCR instruments, eliminating the need for specialized infrastructure. By combining ultrahigh sensitivity, PAM independence, multiplexing preamplification capability, and practical affordability, DHCC provides an accessible platform for ctDNA-based liquid biopsy in clinical settings.

The patient was treated with neoadjuvant immunotherapy using ipilimumab and nivolumab. These findings suggest phenotypic plasticity and immune escape as potential mechanisms of resistance, underscoring the need for integrated histopathological and molecular assessment when evaluating pathological response in rare melanoma variants. As neoadjuvant immunotherapy becomes increasingly incorporated into clinical practice, it is crucial to characterize its impact across the diverse presentations of melanoma and to understand the distinct patterns of pathological response.

Our study demonstrates the superiority of ctDNA harboring melanoma specific mutations over LDH and S100 in identifying patients at risk for recurrence in early melanoma stages in a single center cohort of melanoma patients. Future prospective trials are warranted to confirm this.

Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Notably, the NRAS p.Q61R variant was classified as Class II and may be associated with malignant progression from borderline tumors to invasive carcinoma. These findings underscore the need for long-term surveillance and molecular investigations to clarify tumor behavior, recurrence risks, and therapeutic targets in such rare entities.

Together, these effects bypass intrinsic effector selectivity, allowing canonical RAS to co-opt effectors normally associated with other RAS subfamilies and broaden downstream signaling. This framework explains how inherent effector preferences govern normal signaling and how oncogenic mutations override these constraints to expand effector engagement in RAS-driven cancers.

cfDNA from fine-needle aspiration rinses provides a highly reliable and efficient substrate for molecular testing in metastatic melanoma, outperforming CB-based analysis in terms of sample adequacy. This approach preserves cellular material for ancillary studies and may reduce false-negative results. Prospective studies using broader next generation sequencing panels are warranted to confirm analytical robustness and clinical utility.

Using a longitudinal time-to-event modeling framework, this proof-of-concept study demonstrates the feasibility of kinetic ctDNA-based risk estimation throughout systemic treatment. Both single-point ctDNA measures and their kinetics may serve as indicators of future disease progression.

P2, N=34, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jan 2026 --> Feb 2027