NRAS G12

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, p70S6K 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 of these combinations.

Here, we show that sotorasib, adagrasib, and the RAS-ON inhibitor RMC-6291 are effective in a neuroblastoma cell line altered by KRAS(G12C). Importantly, sotorasib also decreased ERK phosphorylation in a NRAS(G12C)-altered cell line xenograft model; however, this treatment did not prolong survival as a single agent. These results suggest that combinations of targeted agents that include sotorasib may be required for clinical benefit in pediatric patients with H- or NRAS(G12C)-altered malignancies in addition to those with KRAS(G12C)-altered malignancies.

To substantiate the preclinical findings, the utility of MEKi in combination with the autophagy inhibitor hydroxychloroquine was analyzed in patients with KRASG12R mutated metastatic PDAC...Three patients had impressive disease control: two had stable disease of 11 and 22.7 months, and one achieved a partial response with an 83% decrease in tumor size that lasted for 8.9 months. Overall, this work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of PDAC patients most likely to benefit from tailored therapeutic strategies.

This study establishes the first sexual dimorphism-aware phosphoproteomic resource for Ras-driven hepatocarcinogenesis, systematically characterizing conserved and sex-divergent phosphorylation networks. The findings provide preliminary molecular insights into gender disparities in HCC progression and may guide future therapeutic exploration.

NRAS proto-oncogene mutations were detected in 80% of cases, but clinical benefit occurred without mutation. Trametinib is an effective, safe, first-line therapy for KLA/GLA.

To our knowledge, there are no previous reports of end-organ improvement and sustained response to chemotherapy containing an anti-EGFR antibody in a patient with CRC complicated by DCBM and DIC. This case highlights the potential benefits of early and appropriate therapy even in critically ill patients with rare metastatic patterns.

The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.

The farnesyltransferase inhibitor tipifarnib blocked mutant HRAS-PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cells, whereas KRASG12C inhibitors blocked mutant KRAS-MEK signaling and synergized with PI3K inhibitors in KRASG12C-mutated cells. Synergy was abolished in MEFs lacking all RAS proteins and in cancer cell lines in which nonmutated RAS family members were deleted. Our data highlight the critical role of wild-type RAS family members in supporting mutant RAS signaling and its importance as a therapeutic cotarget in RAS-mutated cancers.

P1, N=45, Recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Aug 2025 --> Jul 2026

In addition to proliferation, MAPK signaling influences conversion by regulating Ngn2 activity. Our results highlight the need to tune therapeutic interventions within a non-monotonic landscape that is shaped by genetics and levels of gene expression.

Plasma cfDNA analysis using NGS is feasible and offers insights into alectinib resistance mechanisms. Early detection of resistance-associated mutations may guide personalized treatment strategies. Larger prospective studies are needed to validate these findings.

P1, N=25, Completed, Elicio Therapeutics | Active, not recruiting --> Completed | Trial completion date: Mar 2026 --> Sep 2024