KRAS G13D

P1, N=76, Not yet recruiting, Beijing Youcare Kechuang Pharmaceutical Technology Co., Ltd.

Molecular docking against oncogenic targets (PIK3CA-E545K, ERBB4-Y1242C, KRAS-G13D, PIK3CA-H1047R, and ATM-A112V) identified meta- and para-substituted analogues (4b, 4c, and 4h) as the most favorable binders, while bulky ortho substituents reduced the affinity due to steric effects. Docking against PIK3CA-E545K produced binding energies that qualitatively paralleled several of the measured MCF-7 selectivity indices, with planar aromatic interactions and hydrophobic contacts defining the structure-activity relationships.

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.

The cancer was refractory to regimens extrapolated from rectal cancer management (capecitabine with oxaliplatin, and irinotecan). Pelvic recurrence and osseous metastases were clearly radiosensitive. Tumor molecular profile showed microsatellite stable cancer with KRAS p.G13D and TP53 p.C176W mutations.

We also include a systematic review of cutaneous HS cases, identifying only two cases with underlying hematologic transdifferentiation. The distinct clinical morphology, histopathologic characteristics, and immunohistochemical markers associated with each of these entities highlight a very rare and unique example of histiocytic transdifferentiation in the context of a hematologic malignancy.

USP15 acts as a critical mediator of oncogenic KRAS-driven metabolic reprogramming in NSCLC by promoting glycolysis via the TGF-β/SMAD signaling cascade. These findings uncover a previously unrecognized role of USP15 in linking metabolic regulation to tumorigenic signaling in KRAS-mutant NSCLC and suggest that targeting USP15 may represent a promising therapeutic strategy for this aggressive cancer subtype.

This study suggests codon 13 KRAS mutations may be associated with LR in LARC. However, given the small number patients and events, these findings should be cautiously interpreted until confirmed by larger studies. Preoperative genetic testing for KRAS mutations is suggested to enhance risk stratification.

Molecular docking and MD simulations confirmed strong and stable interactions with CDK6 and KRASG13D proteins. In vivo, 8b exhibited significant tumor growth inhibition in multiple murine models (up to 89.58 % TGI in EAC) with minimal systemic toxicity and favorable pharmacokinetic parameters.

OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. This suggests that other factors, such as the slow plasma terminal phase of the free Pt(II) species from oxaliTEX that prolongs exposure to low drug concentrations, may contribute to the favorable in vivo antitumor activity and therapeutic index of the conjugate. These characteristics demonstrate superiority of oxaliTEX and generate much optimism for its success in future clinical trials.

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.