KRAS G12D

Furthermore, immunocytochemistry revealed co-localization of the site-directed mAbs with endogenously expressed KRAS in cancer cells bearing G12D mutations. The validated high affinity and specificity of these site-directed mAbs highlight their potential for diagnostic applications and therapeutic development targeting KRAS driver mutations.

Additionally, we found that coculturing PLPs loaded with GFP-KRASG12D with tumor cells increased their proliferative capacity at specific PLP concentrations. In conclusion, our study successfully engineered an MEG-01 cell line to produce PLPs carrying oncogenic GFP-KRASG12D simulating the tumor microenvironment, demonstrating the efficient transfer of this oncogene to tumor cells and its significant impact on enhancing proliferation.

This approach yielded a comprehensive model that distinguishes normal pancreatic tissues from pathological features such as pancreatic intraepithelial neoplasia (PanIN), cancerous regions, hemorrhages, and collagen fibers, as well as a streamlined model designed to rapidly identify normal tissues versus pathologically altered regions, including PanINs. These models offer highly accurate diagnostic tools for the early detection of pancreatic malignancies, thus significantly improving the chance for timely therapeutic intervention against PDAC.

CPP-PNA-G12D-1 was effective against a panel of pancreatic ductal adenocarcinoma cell lines and patient-derived xenografts in vivo . These results show promise for an enhanced PNA-delivery peptide conjugate strategy as both a tool for studying tumors driven by oncogenic point mutations and as a potential therapeutic strategy to selectively target mutant cancer cells.

Patients with advanced lung carcinoids harboring AGAs can derive meaningful benefit from genotype-matched targeted therapies, highlighting potential role for NGS in patients with advanced carcinoids.

Moreover, the degradation caused by 11n manipulated the signaling pathways associated with cell apoptosis, metastasis, and invasion to inhibit the tumor growth both in vitro and in vivo. These findings not only generated a useful tool for exploring the potential of targeting SHP2 degradation but also offered promising candidates to develop novel drugs based on the autophagy mechanism.

Thanatosomes revealed periodic acid-Schiff reactivity with diastase resistance, fuchsinophilia with Masson's trichrome stain, and dark blue-black color with Mallory's PTAH stain. This is the first report linking thanatosomes in KRAS-mutant pulmonary adenocarcinoma to apoptosis via cleaved caspase-3 staining.

Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively.

AOH1996 safely and effectively targets TRCs in preclinical PDAC models, with initial clinical evidence supporting its potential for treating chemotherapy-refractory PDAC. Further clinical development is warranted.

Active Wnt signalling is a general mechanism required to promote KrasG12D and p53R172H cell retention and cell survival in vivo. Conclusions RAS mutant cells activate Wnt5a and cell dormancy to avoid cell expulsion and to survive in the adult pancreas.

P1, N=12, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Apr 2025 --> Apr 2027

This review further describes some of the early affirmations on combination strategies with G12Di. We postulate to go beyond 'Drugging the Undruggable' with advanced combination approaches mitigating G12C and G12D inhibitor resistance.

P1, N=63, Terminated, Mirati Therapeutics Inc. | N=386 --> 63 | Trial completion date: Aug 2026 --> Mar 2025 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2026 --> Mar 2025; Formulation challenges

Immunohistochemistry revealed positivity for GATA3, TTF-1, and CD10, and negativity for ER and WT1. Molecular analysis identified a KRAS p.G12D mutation, typical of MLA, and a SMAD4 mutation.ConclusionThis tumor represents the ninth documented example of ovarian carcinoma with distinct components of MLA and low-grade serous neoplasm, SBT or low-grade serous carcinoma, providing valuable insights into the clinicopathological features and molecular characteristics of MLA, and contributing to the understanding of its origin and clinical behavior.

Synergistic interactions between JA and various PDAC chemotherapeutic agents, including oxaliplatin, SN-38, paclitaxel, 5-fluorouracil, and gemcitabine, were observed using the Bliss independence model. These findings highlight JA as a promising therapeutic candidate for PDAC, particularly in the context of KRAS G12D-driven tumors. Further investigations into its pharmacokinetics and clinical feasibility are warranted to explore its full potential in PDAC treatment.

P1/2, N=10, Recruiting, West China Hospital,Sichuan University; West China Hospital,Sichuan University

We show that ABD778, a potent and selective ABHD17 inhibitor with in vivo activity, selectively reduces the growth of NRAS -mutant AML cells in vitro and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901) 7,8...ABD778 augmented the anti-leukemia activity of the pan-PI3 kinase inhibitor pictilisib 9 , the K/N-Ras G12C inhibitor sotorasib 10 , and the FLT3 inhibitor gilteritinib 11 . Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other NRAS -mutant cancers.

Our findings establish the Stmn1-lineage as a pivotal subpopulation for acinar tissue homeostasis and regeneration. The ability of these cells to restore acinar tissue in an ADM-independent manner distinguishes them as a critical regenerative population. This study presents a new paradigm for acinar regeneration and repair in the context of pancreatitis and neoplasia.

KRAS(G13D) models showed reduced sensitivity, particularly with NF1 loss. SHP2+MEK inhibitor combinations also had low SII, with RAS(Q61X) models demonstrating resistance due to NRAS(Q61X) reactivation and impaired SHP2 inhibitor binding.PanKRAS(OFF) selective inhibitors have higher SII than panRAS-GEF(OFF) inhibitors: panKRAS(OFF)-selective inhibitors have a higher SII compared to panRAS-GEF(OFF) inhibitors, offering better tumor-versus-normal cell selectivity.PanRAS(ON) inhibitors have broad but modest SII: While panRAS(ON) inhibitors displayed a broader activity profile, their ability to selectively inhibit mutant RAS signaling over normal cells remained relatively narrow (low SII).Most KRAS-mutant tumors will be insensitive to any single RAS-targeted inhibitor: State- and paralog-selective inhibitors have enhanced activity in the same RAS-MUT cancer models that are also sensitive to RAS-MUT-specific inhibitors, suggesting that most KRAS-MUT tumors will not respond uniformly to any one RAS-targeting inhibitor.SII varies across RAS inhibitors, necessitating tailored therapeutic strategies: The effectiveness of paralog- and state-selective inhibitors depends on specific RAS mutations and cell context, highlighting the need to integrate SII considerations into the development and clinical application of RAS-targeted therapies.

Importantly, targeting PPY enhanced the efficacy of anti-PD-1 immunotherapy in KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx1-Cre) mice, as evidenced by reduced tumor burden on PET-CT imaging and improved survival. This research is expected to provide a novel strategy for improving immunotherapy in PDAC by targeting a key inducer of iCAFs.

We show that PDAC-derived sEVs are differentially enriched in specific lipids associated with cancer phenotype. Our findings highlight that PDAC-derived sEVs are enriched in specific lipids, particularly S1P, which plays a crucial role in promoting cancer progression.

This model can recapitulate the progress of intestinal, pancreatic, liver, lung, and subcutaneous tumors which derive from epithelial cells. This model is suitable for studying the pathophysiology of tumors derived from epithelial cells and may have the potential to test interventions.

Our study combines MRTX1133 with the SHP2 inhibitor SHP099 or PI3K inhibitor Buparlisib, showing synergistic inhibition of pancreatic cancer cell growth and enhanced apoptosis. These combination therapies could improve clinical outcomes for patients with KRAS G12D  mutation in pancreatic cancer.

Apigenin and many other flavonoids showed high binding energies on xanthine oxidase (1.1-1.5 fold of febuxostat) and DNA methyltransferases (1.1-1.2 fold of azacytidine). Apigenin and certain flavonoids also have high binding energies with aromatase (involved in estrogen production) and bacterial infections, i.e., DNA gyrase B and 3R-hydroxy acyl-ACP dehydratase (FABZ). Our findings are pivotal in identifying specific flavonoids that can effectively inhibit targeted proteins, paving the way for the development of innovative flavonoid-based drugs.

Here, we show that ZNF768 deletion was sufficient to repress lung tumor development in a KRASG12D-induced cancer mouse model. Overall, our findings establish ZNF768 as an important protein controlling cell proliferation that could potentially be targeted to reduce tumorigenesis.

Finally, ACSS2 plays a critical role in early KRAS G12V adenoma development, unlike in KRAS G12D adenomas. These findings highlight mutation-specific metabolic reprogramming in KRAS-driven CRC and identify ACSS2 as a potential therapeutic target.

This study reveals RASON as a key oncogenic regulator of KRASG12C signaling, driving lung tumorigenesis and progression, and identifies RASON as a promising therapeutic target for KRASG12C mutant non-small cell lung cancer.

Hyde" where their "Jekyll" side promotes tissue repair while their "Hyde" side drives tumorigenesis. Sustained NF-κB activation drives lineage infidelity, enabling these mutant cells to bypass normal differentiation, remodel the surrounding microenvironment, and ultimately promote tumorigenesis.

FAPα+CD144+endoCAFs can promote metastasis of PDAC via undertaking VM and paracrine through activation of the CD144-β-catenin-STAT3 signalling axis. CAF-targeting siRNA delivery nanosystem can inhibit tumour progression by precisely targeting FAPα+CD144+endoCAFs.

Anaplastic ovarian carcinoma is characterized by KRAS, TP53, and CKDN2A alterations. Novel treatment approaches are needed due to the high rate of platinum-refractory disease.

developed a high-affinity, selective, long-acting, non-covalent KRASG12D-specific inhibitor and, further combined with the proteasome inhibitor carfilzomib, found that this protocol can achieve the purpose of killing mutant cell lines and inhibiting tumor growth in vitro and in vivo. Here, we aim to describe a potential novel therapy for patients with KRASG12D mutations and present the first KRASG12D-specific inhibitor to be proven as clinically effective. Different mutations of KRAS gene and mechanisms of KRAS drug resistance were also discussed.

Combination therapy of iExoKras G12D and anti-CTLA-4 antibodies, but not anti-PD1, revealed robust anti-tumor efficacy via FAS mediated CD8 + T cell anti-tumor activity. This first-in-human, precision medicine clinical trial offers new insights into priming of immunotherapy by oncogenic Kras inhibitor and an opportunistic combination therapy for PDAC patients.

We show a specific synergy of anti-CTLA4 immune checkpoint blockade with Kras* targeting primed by Kras G12D allele specific inhibitor, MRTX1133 and multi-selective pan-RAS inhibitor, RMC-6236, both currently in clinical testing phase. Single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with important clinical implications.

Our results indicate that KRAS mutation subtypes influence immune cell composition and function in the pancreatic cancer microenvironment, leading to varied immunotherapy responses. This underscores the need for personalized immune therapeutics and research models specific to KRAS mutations.

ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

P1, N=47, Terminated, Taiho Oncology, Inc. | N=100 --> 47 | Trial completion date: Jul 2027 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2025 --> Nov 2024; Taiho Oncology as the sponsor of study TAS0612-101, has made a strategic decision to terminate the TAS0612-101 study, taking into consideration the safety profile of TAS0612 and the absence of encouraging anti-tumor activity.

Our findings improve the understanding of lung cancer genetics in a small and homogeneous area of Southern Italy and guide future research. The EGFR and KRAS mutations in NSCLC resected patients from Southern Italy showed a global similar incidence compared to other recently described Italian cohorts of advanced and early-stage NSCLC, with a higher frequency of exon19 EGFR deletions. No prognostic impact was observed for both EGFR and KRAS status, but additional investigations on a larger cohort are needed.

Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.

Finally, therapeutic blockade of KRASG12D spared mutant HSC but reduced the expansion of mutant MPP and their mature progeny. Thus, transforming mutations facilitate their own spread from stem cells by reprogramming MPP, creating a preleukemic state via a two-component stem/progenitor circuit.

In particular, a decrease in stool microbiota diversity and abundance of bacteria known to be involved in short-fatty acids production were observed. PDAC mouse model can be used for further research on microbiota-PDAC interactions and towards more personalized and effective cancer therapies.

However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

These degraders offer a promising alternative to traditional inhibitors by potentially circumventing resistance and enhancing therapeutic precision. This review discusses recent advancements in RAS pathway degraders, with an emphasis on targeting RAS mutations as well as their upstream regulators and downstream effectors for potential cancer treatments.