RAS (Rat Sarcoma Virus)

P3, N=1000, Recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2032 --> Jan 2032

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.

These results contrast with prior tissue-based studies and indicate that bTMB may reflect tumor burden and aggressive disease biology rather than tumor immunogenicity. Prospective studies integrating bTMB with ctDNA fraction, tumor burden metrics, and longitudinal molecular dynamics are warranted to refine its clinical utility.

Structural studies of the D92C variant in complex with the compound BI-1830 uncovered a distinct novel binding pocket, highlighting the inherent plasticity of the region between switch-II and α3, that can accommodate diverse chemical entities in various conformations. This method holds significant potential for advancing drug discovery efforts against elusive targets such as oncogenic RAS mutants.

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.

These findings support the use of anti-EGFR rechallenge strategy aslater-line treatment when tumor shrinkage is a clinical priority. Further evidence from prospective trials is required.

P2, N=18, Terminated, Recursion Pharmaceuticals Inc. | N=60 --> 18 | Trial completion date: Jan 2027 --> Feb 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2027 --> Feb 2025; Study was terminated due to sponsor decision. This decision was not related to safety concerns.

Moreover, reports on the long-term survival of patients with unresectable mCRC with concurrent mutations are lacking. The present study reports a rare case of long-term survival of over 39 months in a patient with mCRC harboring both RAS and BRAF V600E mutations, where chemotherapy alone was effective without surgical resection of the primary or metastatic lesions.

Specifically, we identified the GTP‒Gly/Asp/Val12Ras‒Gln61Ras‒Tyr64Ras‒Ile36Ras‒Ile803RBD pathway that exhibits divergent behavior in wild-type versus mutant systems. The interaction dynamics represented here may serve as a good reference point for studies aiming to develop mutant-specific targeting against tumors harboring Ral overactivity.

First-line treatment with tislelizumab plus XELOX and bevacizumab demonstrated a high ORR and a manageable safety profile in patients with MSS/pMMR, RAS-mutant mCRC. This chemo-immunotherapy combination represents a promising strategy and warrants further investigation in a phase III trial.