RAS mutation

Orthotopic KRAS-mutant xenograft models (LOVO-Luc2 (N = 52) and SW480-Luc2 (N = 52)) were treated with standard-of-care regimens (FOLFOX, bevacizumab, or combination) and longitudinally imaged by CT (N = 104 tumour scans, N = 156 liver scans collected over 4 timepoints)...The most predictive features, GLSZM Gray Level Non-Uniformity, GLRLM Run Length Non-Uniformity Normalized, and GLDM Small Dependence Emphasis, were significantly associated with metastatic burden and survival in a clinical CRC cohort (N = 41), indicating species conservation and translational relevance. Collectively, these data demonstrate that preclinical CT radiomics can identify quantitative imaging features associated with treatment sensitivity and early metastatic progression, supporting translational potential.

P1/2, N=222, Not yet recruiting, Genfleet Therapeutics (Shanghai) Inc.

P1/2, N=83, Suspended, Virginia Commonwealth University | Recruiting --> Suspended

Prognostic accuracy improved when tumor genotype was combined with the expression of activator of HSP90 ATPase activity 1 (AHSA1) and thioredoxin domain-containing 5 (TXNDC5), involved in ER-associated protein folding. These findings define a distinctive proteomic signature in BRAF-mutated CRC, characterized by dysregulated protein folding associated with ER stress and supporting the development of targeted therapies and more precise prognostic models.

We demonstrate RAS-dependency in DIPG targetable by RRSP-DTT-TEM8, a novel, first-in-class pan-RAS biotherapeutic, supporting its potential as a therapeutic strategy for this otherwise untreatable disease.

P1, N=31, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Future efforts should focus on combination therapies, biomarker-driven patient stratification, and the development of targeted delivery systems to overcome toxicity and resistance. A deeper understanding of tumor metabolic heterogeneity will be essential for translating these approaches into clinical practice.

In vivo, β-Lapachone significantly suppressed tumor growth in a syngeneic KRAS-mutant/p53-Null mouse lung cancer model and further potentiated cisplatin-induced antitumor effects. Collectively, these findings identify β-Lapachone as a potent inhibitor of USP22 and validate USP22 inhibition as a key mechanism underlying its anticancer activity in LUAD cells, both in vitro and in vivo.

RAS/RAF mutations may negatively impact metastatic tumor response rates in curative Stage IV rectal cancer patients treated with pTNT. Larger scale studies are needed to verify these results.

This study demonstrated that dynamic changes in plasma RAS mutation status may occur during disease progression in patients with mCRC, potentially reflecting tumor clonal evolution. The observed survival advantage in patients with RAS mutation clearance suggests potential prognostic relevance. Reassessment of RAS status using liquid biopsy at disease progression may provide clinically relevant information; however, these findings should be considered exploratory and require prospective validation in larger cohorts.

To determine combination partners that enhance RAS(ON) mutant-selective inhibition, a drug repurposing screen revealed that KRASG13C models are selectively vulnerable to chemotherapy. Combination of docetaxel with RMC-8839 demonstrated robust anti-proliferative activity in KRASG13C-driven NSCLC models in vitro and in vivo.

Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.