KRAS wild-type

This study detected a significant correlation between the presence of viral agents and KRAS G12D mutations.

P1, N=51, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Jan 2025 --> Jun 2025

The adverse impact of KRAS mutations in BTC is driven by G12 alterations in patients with IHC regardless of resection status, which was not observed in GB or EHC. There are unique comutational partners in distinct BTC subsets. These differences have important clinical implications in the era of KRAS-targeted therapeutics.

These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.

In the overall population, moderate-to-extreme problems were reported in all EQ-5D-5L dimensions (range: overall population, 15.5-39.6%; KRAS G12C, 15.6-46.6%; non-G12C, 7.8-23.1%; WT, 21.1-44.2%). HRQoL was broadly similar across KRAS G12C, non-G12C, and WT subpopulations.

MGMT silencing occurs in a small subgroup of PACs and is enriched in KRAS wild type cases, with a favorable prognostic impact. Our findings provide the rationale to explore combinations of alkylating with DNA damaging agents in MGMT-silenced PAC.

Our research indicates a close association between mutation types and tumor microenvironment in NSCLC, offering insights into personalized approaches for cancer diagnosis and treatment.

P1, N=279, Completed, Jazz Pharmaceuticals | Active, not recruiting --> Completed

Combined administration with KRAS siRNA, MEK1/2 inhibitor trametinib, and NF-κB inhibitor dimethyl fumarate (DMF), suppressed L-OHP- and 5-FU-induced EMT. These results suggest that KRAS/ERK/NF-κB pathway activation is important for EMT induction by L-OHP and 5-FU treatment. Thus, MEK1/2 and NF-κB inhibitors may facilitate the resistance acquisition to L-OHP and 5-FU therapy in KRAS G13D-mutated colon cancer.

P1/2, N=26, Completed, Sellas Life Sciences Group | Active, not recruiting --> Completed | N=90 --> 26

P1, N=325, Active, not recruiting, Exelixis | Trial completion date: Nov 2024 --> May 2027 | Trial primary completion date: Nov 2024 --> Aug 2026

Therefore, in the presence of MSI-H/MMRd and an additional actionable target, we prefer treating with targeted therapy and reserving immunotherapy for later lines. Pt preference has to be taken into consideration at all times though.

These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.

KRAS mutation status did not significantly influence ICI efficacy, although a non-significant trend towards better survival was observed in KRAS-MT patients treated with first-line ICI. These findings contribute to the ongoing research in this field.

This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.

Mechanistically, TMOD3 promoted F-actin polymerization, thereby facilitating the fusion of autophagosomes with lysosomes, increasing the degradation of the ACSL4 protein, and augmenting the ferroptosis-inducing effects of RSL3...Cangrelor, an FDA-approved drug, can target TMOD3...In conclusion, TMOD3 was found to inhibit ferroptosis and induced the resistance to PD-1 antibody by facilitating the fusion of autophagosomes and lysosomes through the promotion of F-actin polymerization in KRAS-mutant PC. TMOD3 was identified as a novel target for PC therapy.

P2, N=58, Not yet recruiting, Xuancheng People's Hospital; Xuancheng People's Hospital of Anhui Province

P2, N=34, Recruiting, National Cancer Institute, Naples | Trial completion date: Sep 2024 --> Sep 2025

KRAS-mut represents a genotypically distinct group of ECs. Overlap exists with genomic predictors (TMB-high, MSI-high) of immunotherapy response, suggesting a possible biomarker-driven combination option with immunotherapy. Clinical trials to evaluate these strategies should be developed.

The KRAS mutation and KRAS G12C mutation confer benefits that impact OS and PFS in NSCLC patients treated with immunotherapy. However, the KRAS G12D mutation negatively impacts OS compared to the KRAS non-G12D mutation. Furthermore, KRAS co-mutations involving STK11 and KEAP1/NFE2L2 are associated with a negative impact on the efficacy of immunotherapy in NSCLC patients.

These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain, independent of other cooperating signals. .

Biochemical and structural analyses of variants identified in a KRAS G12D second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.

No dose-limiting toxicities (DLTs) were observed; however, one patient experienced Grade 2 cytokine release syndrome (CRS) (table 2), managed with tocilizumab...Ongoing analyses include phenotyping of pre- and post-infusion CBNK cells, donor NK cells, and other immune cell types. Conclusions The combination of cetuximab with pre-A+E CBNK cells is safe and demonstrates promising efficacy for treating MRD in CRC.View this table:View inline View popup Download powerpoint Abstract 1457 Table 1 Patient characteristicsView this table:View inline View popup Download powerpoint Abstract 1457 Table 2 Safety dataView this table:View inline View popup Download powerpoint Abstract 1457 Table 3 ctDNA clearance: ad interim report

P3, N=480, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Non-low grade of tumor budding, and high SII level were independently associated with KRAS mutation in CRC. It provides additional references for diagnosis and treatment options for patients with CRC.

These methods have been applied as a proof-of-concept to KRAS and have shown they can predict known cryptic binding sites. Furthermore, we performed ligand-binding simulations of a known inhibitor (MRTX1133) to shed light on the nature of cryptic pockets in KRASG12D and the role of conformational selection vs induced-fit mechanism in the formation of these cryptic pockets.

P2, N=74, Active, not recruiting, Jazz Pharmaceuticals | Trial primary completion date: Aug 2024 --> Jul 2025

We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.

Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.

One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months...One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

P2, N=2, Terminated, Shanghai Henlius Biotech | N=49 --> 2 | Trial completion date: Apr 2026 --> Dec 2023 | Suspended --> Terminated | Trial primary completion date: Aug 2024 --> Dec 2023; Due to poor clinical trial accrual, the study was terminated.

P1/2, N=125, Recruiting, Kahr Medical | Trial completion date: Dec 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

We used the combined chemotherapy of gemcitabine (1,000 mg/m2) + oxaliplatin (135 mg/m2) + nimotuzumab (400 mg). Then, the patients were treated with oral olaparide (600 mg/day) for one year, and survived without tumor progress for more than 1.5 years. These two cases achieved excellent effects of precise chemotherapy, which provided an important reference for the treatment of pancreatic cancer patients with wild KRAS and mutant BRCA.

P1/2, N=301, Recruiting, Eisai Inc. | Phase classification: P1 --> P1/2 | N=181 --> 301 | Trial completion date: Mar 2027 --> Nov 2026 | Trial primary completion date: Mar 2027 --> Nov 2026

The estimated primary completion date of RAMP 301 is 2028, and the estimated study completion date is 2031. ClinicalTrials.gov NCT06072781.

CASPER is easy to implement and is a versatile and reliable method that is virtually adaptable to any point mutation.

After development of acquired resistance, biopsy of one patient's KRAS wild-type, ERBB2 amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD1 immunotherapy combinations.

There was no effect of Kirsten rat sarcoma mutations on local recurrence after surgical radiofrequency ablation or microwave ablation of colorectal liver metastasis in this study. Tumor size and ablation margin remained as independent predictors.

P2, N=58, Active, not recruiting, Gruppo Oncologico del Nord-Ovest | Trial completion date: Jul 2024 --> Dec 2024

This study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies.

P1/2, N=22, Active, not recruiting, Laekna Limited | Recruiting --> Active, not recruiting | N=167 --> 22

P1/2, N=52, Completed, TyrNovo Ltd. | Active, not recruiting --> Completed | N=110 --> 52