RAS wild-type

P1, N=12, Not yet recruiting, VA Office of Research and Development | Trial completion date: Feb 2031 --> Jul 2031 | Initiation date: Feb 2026 --> Jul 2026 | Trial primary completion date: Feb 2031 --> Jul 2031

P2, N=38, Not yet recruiting, Emory University

Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development.

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.

P2, N=37, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2026 --> Jul 2030 | Trial primary completion date: Dec 2026 --> Jun 2026

P2, N=32, Recruiting, Dana-Farber Cancer Institute | N=76 --> 32

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.

Furthermore, mutations induce specific changes in the protein's internal communication networks. These insights into the dynamic properties of oncogenic NRAS mutants provide a robust mechanistic foundation for understanding aberrant signaling and guiding the rational design of novel anti-cancer therapeutics.

Stratified two-stage TMP reliably identifies actionable alterations in PC patients, with potential therapeutic benefit. The proposed TMP algorithm might be as effective, yet more feasible and economic compared with comprehensive upfront testing.

Notably, actionable gene fusions were found to be significantly enriched in KRAS-wt EO-PDACs compared with LO counterparts (4 versus 1, or 36.4% versus 2.4%, P = 0.005). KRAS-wt PDAC diagnosed at a younger age more frequently harbors actionable mutations, highlighting the importance of comprehensive genomic profiling to guide targeted therapeutic interventions in this patient population.

Multiplex immunofluorescence staining demonstrated that BCL-xL inhibition effectively triggered apoptosis in heterogeneous PDX tumor slice models, including models harboring oncogenic BRAF mutations. Our findings suggest that cetuximab-resistant CRC retains apoptotic competence, and that BCL-xL inhibition serves as a robust alternative therapeutic strategy that is largely independent of the tumor mutational profile.

P2, N=477, Suspended, Gruppo Oncologico del Nord-Ovest | Trial completion date: Dec 2027 --> Dec 2029 | Recruiting --> Suspended | Trial primary completion date: Oct 2025 --> Oct 2027