KRAS G12D

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.

Finally, we demonstrate that HNF4α depletion enhances sensitivity to pharmacologic KRAS G12D inhibition. Collectively, our data show that co-expression of opposing lineage specifiers leads to a hybrid identity state that can drive tumor progression and dictate response to targeted therapy in LUAD.

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

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

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.

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.

To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific Kras G12D/+ ( G12D ) mice...Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.

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.

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.

Exposure to the non-selective beta adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551 blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. We show that SIS induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in KC mice subjected to an obesogenic HFCD. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.

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 results indicate that COX-2/PGE2 pathway is activated in the p53-stabilized cells in the missense-type p53 mutant cancer, and secreted PGE2 may transactivate Wnt/β-catenin signaling in neighboring p53-destabilized tumor cells in the intratumor microenvironment. Therefore, targeting stabilized mutant p53 or COX-2/PGE2 pathway may suppress Wnt/β-catenin signaling of both mutant p53-stabilized and destabilized cells, thus can be a possible preventive or therapeutic strategy.

Molecular docking demonstrated that Encorafenib inhibits the V600E variant BRAF protein less effectively compared to its wild-type counterpart. Overall, this study highlights the importance of comprehensive molecular screening and bioinformatics in understanding the mutational landscape of CRC in the Saudi population, ultimately improving targeted drug treatments.

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.

P1, N=100, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Aug 2024 --> Apr 2025

By using Differential Scanning Fluorimetry (DSF) we confirmed several compounds that bind directly to purified p110α. The most potent hits will be followed up by co-crystallization with p110α to aid further elucidation of the nature of the interaction and extended optimisation of these compounds.

Hits were identified using tandem mass spectrometry, and orthogonal validation showed effective inhibition of KRASG12D with IC50 values as low as 25 nM, and excellent selectivity over the wild type form. These findings have the potential to lead to new drugs that target mutant RAS-driven cancers, and provide proof-of-principle for the phosphoestamer chemical platform against PPIs in general - opening up new possibilities in neurodegenerative disease, viral infection, and many more conditions.

In summary, although a KD intervention alone did not prevent pancreatic carcinogenesis, our data suggests that a KD modulates insulin signaling and hepatic lipid metabolism, highlighting its beneficial effects on healthspan and liver function when compared to an HFD.

Primary mesenchymal tumors and neuroendocrine neoplasms were excluded because immunohistochemistry was negative for anaplastic lymphoma kinase (ALK), smooth muscle actin (SMA), desmin, CD34, signal transducer and activator of transcription 6 (STAT6), S100, HMB45, CD117, discovered on GIST-1 (DOG1), CD56, progesterone, and synaptophysin...This study highlights the clinical characteristics, diagnosis, and treatment of rare pancreatic cancer, emphasizing the importance of molecular testing and histopathological biomarkers in personalizing treatment. It also provides insights into promising therapeutic approaches for similar cases with an unusual presentation.

Overexpression of DDX60, which competitively binds to dsRNA to prevent RISC-mediated degradation, or targeting of KRASG12D elevated dsRNA levels, resulting in viral mimicry activation and potentiation of ICI treatment. These results establish KRAS as a promising target to sensitize immune "cold" tumors to ICI therapy and demonstrate the potential role of oncogenic mutations in viral mimicry evasion during tumorigenesis.

Thus, the therapeutic effectiveness appeared to largely depend on cancer-cell MHC-I expression, triggering CD8 T cell effector memory-driven responses against tumor cell antigens. Identifying the differential RT response to MHC-I induction may serve as a predictive marker for stratifying patients that are most likely to benefit from this combination therapy.

KDA11-01 and KDA11-02 demonstrated exceptional specificity for the HLA-A*11:01-restricted KRAS G12D7-16 epitope, significantly inducing IFN-γ release and eliminating tumor cells without cross-reactivity or alloreactivity. The successful development of KDA11-01 and KDA11-02 introduces a novel and precise TCR-based therapeutic strategy against KRAS G12D mutation, showing potential for significant advancements in cancer immunotherapy.

Overlap of the Oncopig LC transcriptome with human LC transcriptome was noted. This pig model is expected to have high clinical translatability to the human LC patient.

This Patent Highlight explores recent cancer treatment and monitoring advancements, focusing on selective KRAS inhibitors targeting mutations like G12C and G12D alongside germline epitope burden analysis. These innovations offer enhanced therapeutic precision and personalized monitoring, improving the prediction of cancer relapse and tailoring treatment strategies to individual patient profiles, significantly advancing the field of precision oncology.

Treatment of normal pancreatic duct and pancreatic cancer cells with sodium butyrate also upregulated pan-Kcr expression while reducing cell proliferation. Our findings reveal the pivotal role of dietary factors in the carcinogenesis of the pancreas and support further clinical studies of FMD as an antineoplastic therapeutic measure.

These findings suggest Ptf1a haploinsufficiency in Ptf1acreERT mouse models promotes KRASG12D priming of genes for promotion of PDAC.

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.

A detail estimation of KRASG12D mut mCRC patients' characteristics and expected outcomes may be useful when planning future studies in this subgroup. The high prevalence of PI3K/PTEN/Akt pathway activating alterations may affect the efficacy of targeted strategies.

Our findings support the concept that, in the context of obesity, ω-3 FA have protective effects during early-stage pancreatic carcinogenesis through the regulation of intestinal permeability and endotoxemia.

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.

Our data highlight a unique combination treatment vulnerability and suggest that patient selection strategies for combination approaches using direct KRAS inhibitors should be i) contextualised to individual RAS mutants, and ii) tailored to their downstream signaling.

P2, N=20, Not yet recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

P1/2, N=181, Not yet recruiting, Zhongshan Hospital ,Fudan University; Zhongshan Hospital ,Fudan University

Recently, an emergency approval from the US-FDA has been issued for KRASG12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.

Our data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations.

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.

Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

Importantly, circPNIT-loaded CD109+ EVs are established to dramatically promote PNI in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mouse model. Collectively, the findings highlight the mechanism underlying how EV-packaged circRNAs mediate the PNI of KRAS-mutant PDAC cells through the Rab5B endosomal bypass, identifying circPNIT as an effective target for the treatment of neuro-metastatic PDAC.

Compared to WT, tumor growth was attenuated in Pld1-/- mice by 39%, whereas treatment of Pld1-/- mice with gemcitabine reduced tumor growth by 79%...Mechanistically, the effect of PLD on tumor growth is mediated, partly, by the FAK pathway. In conclusion, while PLD1 is a critical regulator of pancreatic xenograft and allograft growth, playing an important role at the tumor and at the microenvironment levels, inhibition of PLD1 and PLD2 are necessary to reduce pancreatic carcinogenesis in KC mice, and might represent a novel therapeutic target.

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.

Analyses of large cancer databases indicate that mtDNA copy number is also important in human lung cancer. Our study thus reports experimental evidence for a tumor-intrinsic causative role for mtDNA in lung cancer progression, which could be exploited for development of future cancer therapies.