KRAS wild-type

Our findings indicate that a monoallelic oncogenic KRAS can confer dysregulated expansion characteristics to non-transformed HPCs, which may constitute a pathological condition in RALD hematopoiesis. The use of iPSC-based screening platforms will lead to discovering treatments that enable selective inhibition of RAS-mutated HPC clones.

We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors. Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.

In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Our data demonstrate that RAS mutations do not affect outcome in rego-treated patients as well as TFD/TPI-treated patients. Nevertheless, a trend toward a higher efficacy of rego in RAS-mutated (in particular codon 12, rare RAS mutations, and G12D) patients has been recorded. The rego-TFD/TPI sequence seems to be superior to the reverse sequence in patients carrying an RAS codon 12 mutation, although the impact of other factors as disease burden or performance status cannot be excluded.

Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.

Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

P1, N=51, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Feb 2024 --> Jul 2024

Similar competition-based assays can be run with small molecule interactors, GEF/GAP domains, or regulatory enzymes that drive posttranslational modifications. Such efforts bring in vitro interaction experiments in line with more complex cellular environments.

Accurate pathological diagnosis is prognostically valuable. The histological features of enteroblastic differentiation, elevated serum AFP levels, and the expression of oncofetal proteins play an important role in the tumor diagnosis.

Furthermore, based on the KRAS mutation-associated gut microbiota, the RF model exhibited promising potential in the prediction of KRAS mutation status for CRC patients. Overall, the findings of our study offered fresh insights into microbiological research and clinical prediction of KRAS mutation status for CRC patients.

P1/2, N=107, Completed, NuCana plc | Recruiting --> Completed | N=225 --> 107 | Trial completion date: Nov 2023 --> Mar 2024 | Trial primary completion date: Nov 2023 --> Mar 2024

P2, N=182, Active, not recruiting, NuCana plc | Recruiting --> Active, not recruiting

P1, N=181, Recruiting, Eisai Inc. | Trial completion date: Oct 2024 --> Mar 2027 | Trial primary completion date: Oct 2024 --> Mar 2027

Meanwhile, mannose-binding lectin (rRSL [Ralstonia solanacearum] and rBC2LA [Burkholderia cenocepacia]) signals were higher while those of galactose-binding lectins (rGal3C and rCGL2) were lower in the KRAS mutants. We demonstrated here that PDAC 3D-cultured organoids with KRAS mutations were dominantly covered in increased fucosylated glycans, pointing towards novel treatment targets and/or tumor markers.

Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

P=N/A, N=25, Recruiting, National Cancer Institute, Naples | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=34, Recruiting, National Cancer Institute, Naples | Trial completion date: Jan 2024 --> May 2024 | Trial primary completion date: Jan 2024 --> May 2023

KRAS-mutated colorectal liver metastases showed more aggressive tumor biology with inferior overall survival and disease-free survival after liver resection. Although R0 resection was not associated with improved oncologic outcomes in the KRAS-mutated tumors group, it seems to be of paramount importance for achieving prolonged long-term survival in KRAS wild-type tumors.

We present two applications to demonstrate the capabilities of our assay: maleimide-biotin labeling of a KRAS4BG12D cysteine mutant panel and treatment of three KRAS4B proteins (WT, G12C, and G13C) with small molecule compounds. Our results show the time- or concentration-dependence of KRAS4B-compound engagement in context of the intact protein molecule while directly mapping the compound binding site.

This study suggests that chemotherapy rechallenge may provide a survival benefit in the third-line treatment of mCRC. However, patient characteristics, such as sex and ECOG PS, should also be considered in treatment decisions. Further prospective studies are required to confirm our findings.

Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).

P3, N=464, Active, not recruiting, GERCOR - Multidisciplinary Oncology Cooperative Group | Recruiting --> Active, not recruiting | Trial completion date: Jun 2021 --> Dec 2024 | Trial primary completion date: Jun 2021 --> Jul 2023

P1/2, N=277, Active, not recruiting, Karyopharm Therapeutics Inc | Trial completion date: Aug 2024 --> Dec 2024

This study analyzes the effect of carbamazepine on early-stage autophagy via ULK1 as well as simulates the docking of carbamazepine on KRAS, depending on the mutation status. Our study highlights the therapeutic uses of carbamazepine on cancer, and we propose that carbamazepine in conjunction with other chemotherapies may prove useful in targeting KRAS-mutated colorectal cancer.

P2, N=24, Recruiting, Immunovative Therapies, Ltd. | Phase classification: P2b --> P2 | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

P2, N=74, Active, not recruiting, Jazz Pharmaceuticals | Recruiting --> Active, not recruiting | N=362 --> 74

The limit of detection was as low as 10 amol, with the system functioning well in physiological media. In particular, this system allowed us to resolve genetic mutations in the KRAS gene in colorectal cancer, suggesting its high potential in clinical diagnosis and personalized medicine.

KRASm are associated with worse overall survival in PD-L1 negative NSCLC; however, this association is largely driven by comutations with STK11 and KEAP1, which are enriched in PD-L1 negative tumors.

P2, N=14, Active, not recruiting, Diwakar Davar | Trial completion date: Sep 2027 --> Aug 2025 | Trial primary completion date: Sep 2025 --> Dec 2024

Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.

The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

The CT-based radiomics nomogram demonstrates the capability to effectively predict KRAS mutation in CRC patients and stratify their prognosis preoperatively.

P2, N=171, Recruiting, NuCana plc | Trial completion date: Dec 2024 --> Mar 2025 | Trial primary completion date: Jun 2024 --> Sep 2024

Finally, multiplexed single-cell immunohistochemical analysis of a 25 patient PDAC tissue microarray revealed a relationship between decreased variance in Spearman r correlation for ITGA1 and PLK1 expression within the tumor cell compartment of PDAC in patients with advanced disease stage, and elevated expression of both ITGA1 and PLK1 in PDAC was found to be associated with decreased patient survival. Taken together, this work uncovers new therapeutic vulnerabilities in PDAC that are relevant to the progression of this stromal cell-rich malignancy and which may reveal strategies for improving patient outcomes.

Although they are rare, the therapeutic and diagnostic importance of these genomic events should not be underestimated, highlighting the need for quality-ensured molecular diagnostics in the management of cancer. Herein we review the existing literature on the role of fusion genes in pancreatic tumors and their clinical potential as effective biomarkers and therapeutic targets.

P1, N=325, Active, not recruiting, Exelixis | Trial primary completion date: Nov 2023 --> Nov 2024

P1, N=715, Recruiting, Taiho Pharmaceutical Co., Ltd. | N=367 --> 715 | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

P2, N=24, Active, not recruiting, UNC Lineberger Comprehensive Cancer Center | Trial primary completion date: Jan 2026 --> May 2023

Anti-CD20 [225Ac]Ac-macropa-rituximab was developed and used as a nonspecific radioimmunoconjugate. Compared with untreated mice, [225Ac]Ac-macropa-nimotuzumab more than doubled (16 vs. 41 d) the median survival of mice bearing SW620 xenografts. [225Ac]Ac-macropa-nimotuzumab is effective against KRAS mutant and BRAFV600E mutant CRC models.

Incorporation of SB-T-121605 and SB-T-121606 into in vivo therapeutic regimens containing paclitaxel was effective in suppressing tumor growth in Paca-44 tumor-bearing mice at small doses (≤3 mg/kg). SB-T-121605 and SB-T-121606 in combination with paclitaxel are promising candidates for the next phase of preclinical testing.

Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4).

P1, N=51, Active, not recruiting, Institut de Recherches Internationales Servier | Recruiting --> Active, not recruiting