KRAS mutation

The feature-based fusion model DLRexpand10_FB can be employed to predict KRAS gene mutations based on pretreatment endorectal ultrasound images of rectal cancer. The integration of peritumoral regions enhanced the predictive performance of both the radiomics and deep learning models.

This study highlights the importance of a comprehensive diagnostic approach for accurately identifying endometrial MLA and for pathologists to be aware of papillary and ductal patterns in endometrial carcinoma assessment. Further exploration into the molecular landscape of MLA is essential for refining diagnostic criteria and developing targeted therapies.

Post-transfection, the KRAS-ERK pathway was downregulated, resulting in significant increases in cell apoptosis and inhibition of cell migration. Taken together, this study reveals a new and promising formulation for CRISPR delivery as potential lung cancer treatment.

A multimodal approach to this patient's management appeared to contribute to his long-term survival of nearly 10 years from the initial diagnosis. Multidisciplinary management, including the use of additional biomarkers, may enhance survival rates in other similar cases with advanced disease resistant to differing therapies, and with potentially poor prognosis.

Here, we review the history of brain AVMs, their treatments, and recent advances in uncovering the pathogenesis of sporadic brain AVMs. We specifically focus on the latest studies suggesting that pharmacologically targeting the KRAS/MEK pathway may be a potentially efficacious treatment for sporadic brain AVMs.

Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.

The top 10 mutations that most commonly accompanied PIK3CA variations were KRAS, NF1, TP53, EGFR, PTEN, BRAF, KIT, CDKN2A, SMARCA4, and ATM mutations, respectively. PIK3CA variations, along with other gene variations, may influence cancer progression and thus may play a crucial role in the determination of targeted treatment strategies.

Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.

The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted.

KRAS inhibitors and other emerging alternative treatments are also discussed, as combining these drugs with immunotherapy may serve as a promising first-line treatment for KRAS-mutated NSCLC in the future. We hope that this review will assist in first-line treatment choices and shed light on the development of novel agents for KRAS-mutated NSCLC.

Our results confirm cancer-kidney crosstalk in specific cancer types. In the era of precision medicine, further research is essential to identify at-risk oncology populations, enabling early detection and management of renal complications.

Mixed NET/non-NET tumors with distinct histology and molecular profiles might be better classified as collision tumors rather than MiNENs.

Primary colonic SRCC is a rare malignant tumor with atypical clinical symptoms, and timely identification and intervention are crucial for improving the prognosis.

P1, N=7, Terminated, Mirati Therapeutics Inc. | Completed --> Terminated; The decision was made to terminate this study to further enrollment, as of 08 March 2022. The decision was made primarily due to a change in development strategy.

P1/2, N=386, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting

The responsiveness of gastrointestinal stromal tumors to imatinib requires validation via molecular testing. Patients diagnosed with pancreatic cancer may see enhanced survival rates by targeted therapy addressing microsatellite instability and BRCA mutations. In bile duct malignancies, especially intrahepatic cholangiocarcinoma of the small duct variant, the analysis of IDH1 mutations and FGFR2 fusions presents new treatment prospects.

Oncogene mutations such as KRAS G12V and EGFR may have implications for cancer surveillance strategies and inform future treatment trials of stage I NSCLC.

EGFR mutations, especially rare variants (G724A, L747P, Q701 L, G719C, V769 L and S768I), exhibited significant enrichment in the non-AM group (P<0.001)...Meanwhile, patients with adrenal metastases harboring ALK or KRAS mutations have a poor prognosis and require more aggressive treatment. The TNF and TGF-β pathways might be associated with adrenal metastasis.

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

Thus, NCRT does not seem to induce a relevant number of new driver mutations or mutational burden. Genetic profiling implies the potential to support tumor-informed approaches and outcome estimation in future.

Our results indicate that 14-gene RNA-level assay is correlated with specific genetic mutations, including TP53, KRAS, and LRP1B. These insights provide a stronger foundation for integrating molecular risk assessment with clinical and imaging data, offering more comprehensive information to guide more targeted and effective adjuvant therapy strategies in the future management of lung cancer.

The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration). NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.

The LCS6 region alteration of the KRAS may play a key role in further cancer progression, and more research is needed to fully understand the mechanisms by which the LCS6 alterations promote cancer progression.

We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network.

Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models. Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS-mutated, metastatic CRC.

P1, N=21, Terminated, Navire Pharma Inc., a BridgeBio company | N=45 --> 21 | Trial completion date: Jan 2025 --> Jul 2024 | Recruiting --> Terminated; Business reasons

P1, N=72, Terminated, Navire Pharma Inc., a BridgeBio company | N=130 --> 72 | Trial completion date: Feb 2025 --> Jul 2024 | Active, not recruiting --> Terminated; Business decision

P1, N=28, Terminated, Navire Pharma Inc., a BridgeBio company | N=85 --> 28 | Trial completion date: Jun 2025 --> Aug 2024 | Recruiting --> Terminated; Business Reasons

SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.

Additionally, Sotorasib increased TXNIP expression by regulating the RAS/RAF/ERK axis. This study uncovers the mechanism by which Sotorasib inhibits glucose metabolism in KRASG12C mutant bladder cancer cells and suggests a potential therapeutic benefit for the treatment of KRASG12C mutant bladder cancer.

Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRASG12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.

Although once thought to be "undruggable", KRAS p.G12C inhibitors such as sotorasib and adagrasib have been developed. This paper focuses on adagrasib, the second KRAS p.G12C inhibitor to obtain regulatory approval by the FDA and describes the details on its study design, development and current place in therapy.

Despite being in early stages, research on KRAS silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments. In conclusion, this review underscores the evolving landscape of KRAS silent mutations, advocating for further exploration to bridge fundamental biology with clinical applications in oncology.

P=N/A, N=75, Recruiting, Peking Union Medical College Hospital | N=50 --> 75 | Trial completion date: Nov 2023 --> Dec 2025 | Trial primary completion date: Oct 2023 --> Jan 2025

Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.

A high prevalence of HER3 expression was observed in pancreatic cancer patients after chemotherapy. Our findings indicate that HER3 is a potential therapeutic target for pancreatic cancer, deserving further clinical investigation.

We tested this hypothesis in multiple preclinical PDAC models receiving MRTX1133, an investigational new drug specific for KRAS G12D mutation...Our data demonstrate the abilities of DWI, DCE and MTR derived imaging markers to detect the early (48h) cell death, pronounced stromal changes and development of resistance to KRASi. This study has high translational relevance by testing clinically ready MRI methods, an IND and a genetic engineered mouse model that recapitulates saline features of human PDAC.

P1, N=498, Recruiting, Genentech, Inc. | Trial completion date: Nov 2024 --> Mar 2026 | Trial primary completion date: Nov 2024 --> Mar 2025

The incidence of MAP2K1 mutations was higher in the current study than in previous studies (Garces et al. 2017), though not statistically significant, at 29% (4/14) compared to 16% (8/49; p=0.15).These results highlight the value of stringent tissue microdissection for identifying targetable molecular alterations in RDD and suggest that such approaches may help uncover additional neoplastic drivers and/or mutations implicated in therapeutic resistance.

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.

Although current first- and second-line therapies stratify for KRAS/NRAS/BRAF mutations, microsatellite instability, tumour location and co-morbidities, the therapeutic mainstay for the first- and second-line treatment of the majority of patients consists of 5-fluorouracil (5-FU)-based chemo-immunotherapy. By exchanging the chemotherapeutic combination partner from oxaliplatin to irinotecan or vice versa, plus the additive anti-epidermal growth factor receptor/anti-vascular endothelial growth factor antibody, the negative factor of non-response to first-line therapy could not be overcome by second-line treatment in this study population. These findings must be confirmed in larger studies, but indicate the need for novel treatment options, especially for patients not responding to first-line 5-FU-based chemo-immunotherapy.