NRAS G13

Across a CRC panel that included SNU-C5/WT and its 5-fluorouracil- and oxaliplatin-resistant derivatives, HT-29 (KRAS-wild-type), and HCT-8 and LoVo (KRAS-mutant), co-immunoprecipitation showed that PrPC forms complexes with the 37/67 kDa laminin receptor (RPSA), with PrPC-RPSA association particularly increased in KRAS-mutant HCT-8 and LoVo cells. Taken together, these findings suggest that extracellular PrPC supports RAS-AKT signaling, proliferation, and tumor-associated angiogenesis in KRAS-mutant colorectal cancer, and that PrPC neutralization additively enhances 5-fluorouracil activity in KRAS-mutant models. The data provide a preclinical basis for evaluating PrPC antibodies in combination with fluoropyrimidine-based regimens in patients with KRAS-mutant CRC.

For patients receiving cytarabine-based front-line chemotherapy, those with RAS mutations had shorter median OS compared to RAS-wild-type AML (27.1 vs. 122.2 months, p < 0.001)...Although 80 (66.1%) of 121 total RAS mutations were found in codons G12 or G13, most substitutions were G12D or G13D, which are not targetable by commercial RASG12C inhibitors. This study sheds light on prognostic implications of RAS mutations and may inform extension of the therapeutic reach of RAS inhibitors to AML.

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

Instead, some cases may reflect adult-onset RASopathies or early clonal proliferations with distinct biological behavior. Recognition of such cases warrants refinement of diagnostic criteria and may influence therapeutic decision-making.

Histopathological evaluation may aid risk stratification alongside KRAS status. Prognostic assessment in clinical settings should take both TNM staging and KRAS status into account.

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.

KRASmt and NRASmt are seen in 49% and 4% of mCRC, respectively. No clinically relevant differences were observed between different RASmt. KRASmt is a common subgroup for which the outcome hopefully can be improved with newly developed drugs.

Sensitivity to mutant-specific inhibitors largely overlapped with sensitivity to state-selective agents, suggesting that most RAS-mutant tumors will respond poorly to any currently available RAS inhibitor. Implications: Determining the signaling inhibition index (SII) can inform the design and clinical application of RAS-targeted therapies to improve tumor selectivity and therapeutic outcomes.

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

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.

The most frequent NRAS mutations were Q61K (19.7%), G12D (19.1%), and G12V (12%). This study provides a large-scale, real-world dataset of KRAS and NRAS mutation profiles in Turkish mCRC patients, contributing significantly to the understanding of the genetic characteristics of mCRC in this population.

KRAS(G13D) models showed reduced sensitivity, particularly with NF1 loss. SHP2+MEK inhibitor combinations also had low SII, with RAS(Q61X) models demonstrating resistance due to NRAS(Q61X) reactivation and impaired SHP2 inhibitor binding.PanKRAS(OFF) selective inhibitors have higher SII than panRAS-GEF(OFF) inhibitors: panKRAS(OFF)-selective inhibitors have a higher SII compared to panRAS-GEF(OFF) inhibitors, offering better tumor-versus-normal cell selectivity.PanRAS(ON) inhibitors have broad but modest SII: While panRAS(ON) inhibitors displayed a broader activity profile, their ability to selectively inhibit mutant RAS signaling over normal cells remained relatively narrow (low SII).Most KRAS-mutant tumors will be insensitive to any single RAS-targeted inhibitor: State- and paralog-selective inhibitors have enhanced activity in the same RAS-MUT cancer models that are also sensitive to RAS-MUT-specific inhibitors, suggesting that most KRAS-MUT tumors will not respond uniformly to any one RAS-targeting inhibitor.SII varies across RAS inhibitors, necessitating tailored therapeutic strategies: The effectiveness of paralog- and state-selective inhibitors depends on specific RAS mutations and cell context, highlighting the need to integrate SII considerations into the development and clinical application of RAS-targeted therapies.