KRAS G12D

Our findings highlight the potential of Y126S as a promising BsAb-based immunotherapy strategy for PDAC by remodeling the desmoplastic and immunosuppressive TME.

Finally, we demonstrate that HNF4α depletion sensitizes LUAD cells to KRASG12D inhibition. Collectively, our data show that coexpression of opposing lineage specifiers is a novel mechanism of identity dysregulation in LUAD that influences both tumor progression and response to targeted therapy.

Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.

Defining how KRAS mutants drive distinct outcomes in human pancreatic cancer is critical for developing allele-specific therapeutic approaches. This study unveils a hierarchy among KRAS G12D , KRAS G12V , and KRAS G12R to drive tumor initiation, owing to heterogeneous activation of EGFR, PI3K/AKT, and RAC1 signaling, thus revealing mutation-specific evolutionary paths in pancreatic tumorigenesis.

KRAS variants were significantly associated with poor prognosis and unfavorable therapeutic outcomes in BTC patients and may serve as potential prognostic and predictive factors.

These findings indicate that the combinatorial strategy effectively bridges innate and adaptive immunity. In conclusion, this study highlights the potential of nanocarrier-based immunotherapy to enhance PDAC immunity by integrating ICD induction with systemic immune reprogramming, offering a promising avenue for improving treatment outcomes.

However, no marketed drugs inhibiting the KRASG12D mutation against pancreatic cancer are currently available. Thus, in this review, we highlight structure-activity relationship (SAR) studies targeting KRAS-G12D with small organic molecules under investigation against pancreatic cancer.

In combination with an oncogenic KRAS G12D mutation, RalGAPβ deficiency leads to a dramatic shortening of tumor latency and median survival. Our results highlight an important role of RalGAP/Ral signaling in upholding acinar cell identity and preventing pancreatic cancer development.

P2, N=40, Not yet recruiting, The Second Affiliated Hospital Zhejiang University School of Medicine; The Second Affiliated Hospital Zhejiang University School of Medicine

P1/2, N=72, Not yet recruiting, Sun Yat sen University Cancer Center; Sun Yat-sen University Cancer Center

However, ZNF768 overexpression was not sufficient to promote 3-methylcholantrene-induced fibrosarcoma and KRASG12D-induced lung adenocarcinoma in mice. Overall, we report the generation of a conditional mouse for ZNF768 overexpression and reveal that forcing ZNF768 expression is not sufficient to alter tumour development in mice.

An initial response to chemotherapy, such as Gemcitabine (GEM) alone or in combination with other chemotherapies, is often followed by emergent resistance, underscoring the urgent need for targeted therapies...The studies suggest that TM targets K-Ras G12D -dependent multiple signaling pathways such as eIF4E, STAT3, and STAT5 activities and CCN1 to promote its anticancer efficacy. Together, these studies reveal the potential of simultaneously targeting a K-Ras G12D -dependent signal and CCN1 with first-line chemotherapy and provide a rationale for future clinical testing of NP TM for PDAC therapy.

We investigated the activity of two CLK inhibitors, cirtuvivint and CC-671, and the LSD1 inhibitor iadademstat alone and in combination with anticancer drugs or investigational agents...These agents included the XPO1 inhibitor, eltanexor, and the KRAS G12D specific inhibitor MRTX-1133 which had activity in tumor lines harboring the KRAS G12D mutation. LSD1 inhibition was effective with ubiquitin proteasome pathway inhibitors. The full data sets are available on PubChem.

Haematologic, biochemical, and coagulation parameters were analysed for Oncopigs under 6 months of age, over 6 months, and collectively for Oncopigs within a year of age. By providing comprehensive data on growth, haematologic, and serum biochemical parameters, this study provides a critical resource for researchers utilizing Oncopigs as large animal models for cancer research and other translational studies.

Here, we demonstrate that BET inhibition is effective in PDAC with acquired resistance to KRAS inhibitors. As BET inhibitors are under clinical testing, the combination of KRAS and BET inhibitors warrants consideration in PDAC patients.

Agents such as Sotorasib, Adagrasib, and Divarasib exhibit notable efficacy against KRASG12C mutations, particularly in NSCLC, with combination strategies significantly improving outcomes, especially in CRC. However, substantial challenges remain, including optimizing clinical trial designs, particularly in early-phase trials, and integrating pharmacodynamic tools to refine dosing and treatment schedules, thus achieving an optimal balance between efficacy and patient tolerability. This review summarizes recent therapeutic advancements, highlighting the clinical development of KRAS-specific inhibitors, and emphasizes future strategies involving a combination of mutant-specific and broader mutant-independent approaches to overcome resistance, thereby offering promise for more durable cancer control and expanded patient eligibility.

This study identified the pAKT-pPCK1-pLDHA-SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin-based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.

Moreover, with a similar strategy, we engineer compact versions of hpOsCas12f1 (458 aa) from enOsCas12f1 and hpAsCas12f1 (447 aa) from AsCas12f1-HKRA, both of which display increased DNA cleavage activity, with hpAsCas12f1 also showing improved gene activation capability. Therefore, we develop activity-increased miniature hpCasMINI, hpOsCas12f1 and hpAsCas12f1 nucleases, which hold great potential for gene therapy in the future.

Body weight normalization slowed obesity-accelerated pancreatic carcinogenesis, in part, by affecting inflammatory and cell signaling pathways, reducing epoxy metabolites, and modulating the gut microbiome.

An anti-CHI3L1 monoclonal antibody was administered to target these macrophage populations, and the treatment resulted in suppressed tumor growth, metastatic progression, and protected body weight. Our results support the role of pancreatic tumor-associated macrophages in mediating skeletal muscle wasting and provide a clinically relevant mechanism of progression from the pre-cachectic state to the cachexia onset.

This study identifies KRASG12D as a clinically and pathologically distinct LUAD subtype, characterized by more aggressive histologic features, a unique co-mutation profile, and independently poorer survival outcomes compared to EGFR-mutant tumors. These findings support the need for refined molecular classification of LUAD and underscore the prognostic importance of KRASG12D mutations in risk stratification and clinical management, particularly in early-stage disease.

In in vivo experiments, the combination therapy markedly delayed tumor growth compared to either therapy alone. Therefore, the combination of avutometinib and MRTX1133 may represent a promising therapeutic approach for KRASG12D-mutated pancreatic cancer.

A high index of suspicion of disease recurrence in the donor lungs should be maintained in these patients. Further research is required to understand the optimal screening, treatment, and follow-up of these patients.

Limiting BCAA intake not only suppresses tumor growth in KRAS-mutant CRC but also enhances the efficacy of the KRAS G12D inhibitor MRTX1133 and the monoclonal antibody bevacizumab. Our findings reveal a previously unknown regulatory mechanism of ECHS1 in CRC and offer new potential therapeutic targets.

While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds...Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development.

These findings provide mechanistic insights into KRAS-driven malignancy and highlight LZTR1 and LAMTOR1 as potential therapeutic targets. The study further lays a foundation for developing mutation-specific strategies to counteract KRAS oncogenic signaling.

P1, N=100, Recruiting, Institut de Recherches Internationales Servier | Active, not recruiting --> Recruiting

Our results corroborate the anti-cancer effects of dauricine against lung adenocarcinoma with in vivo and in vitro analyses. Our findings also provide mechanistic evidence that links the impact of dauricine to cell cycle blockage and ROS-mediated apoptosis.

To overcome NFκB2-driven resistance mechanisms, we explored a triple-targeting strategy that addresses metabolic and genomic plasticity in addition to actively intercepting cell division. This approach combines MRTX1133, Bedaquiline, and the NFκB2 inhibitor SN52, offering a novel therapeutic avenue to treat aggressive pancreatic cancer and potentially improve patient outcomes.

The patient was treated with carboplatin and pemetrexed, followed by sotorasib upon disease progression. RNA sequencing and additional analyses revealed increased VEGF-A expression in metastatic lymph node lesions, suggesting a role in sotorasib resistance. These findings provide insights into the potential molecular mechanisms underlying treatment resistance in KRAS p.G12C-mutant IMA.

The most frequent NRAS mutations were Q61K (19.7%), G12D (19.1%), and G12V (12%). This study provides a large-scale, real-world dataset of KRAS and NRAS mutation profiles in Turkish mCRC patients, contributing significantly to the understanding of the genetic characteristics of mCRC in this population.

Altogether, these results indicate that the Twist1 transactivation domain is required for Twist1-dependent acceleration of lung tumorigenesis via MYC and nominate MYCi975 as a means to activate latent OIS programs. MYC targeting strategies could limit pro-tumorigenic programs and serve as a therapeutic for TWIST1-overexpressing NSCLCs.

Mechanistically, NRF2 suppresses IPMN formation through redox-independent transcriptional repression of SPDEF and MUC6, key markers of IPMN. These findings establish NRF2 as a lesion-specific regulator of pancreatic tumorigenesis, providing new molecular insights into PDA progression and potential biomarkers for early detection and risk stratification.

Moreover, we predict that gefitinib, afatinib, erlotinib, and selumetinib could serve as potential co-targeting therapies for KRAS mutations. KRAS mutations serve as independent prognostic risk factors in PAAD, and targeting these mutations may offer a promising therapeutic approach to improve patient outcomes.

This dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.

Currently, four KRASG12C-specific inhibitors, namely sotorasib, adagrasib, fulzerasib and garsorasib, have garnered regulatory approval. PROTAC-mediated KRAS and SOS1 degradation has been emerged as a promising strategy to overcome these issues, and achieved rapid progress in the recent years. This article provides an overview of the chemical structures, design strategies, structure-activity relationship (SAR) studies as well as in vitro and in vivo activities of the PROTACs degrading KRAS and SOS1, and sheds light on future challenges and opportunities to accelerate the development of new chemotherapies for KRAS-driven cancers.

These findings demonstrate that ST6GalNAc-I-mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

Recent advances have led to developing small molecule inhibitors that selectively target the active GTP-bound state of KRAS G12D, blocking downstream signaling and oncogenic activity. These compounds show strong therapeutic potential.

TAT-CRE induced lung tumors present differences in micro-vessels and macrophages but with corresponding tumor onset and growth characteristics compared to adenoviral-Cre recombinase induced lung tumors. Taken together, TAT-CRE is a valuable genetic engineering safety level S1 alternative for cancer induction and may be implemented in other cancer models than lung cancer.

Analysis of human LUAD data demonstrated negative correlations between STAT3 and Th1/DC infiltration, with DC infiltration also conferring improved survival in LUAD patients with low STAT3. Our results highlight the importance of STAT3 in driving early tumorigenesis and offer a preventative treatment window for high-risk individuals and patients with early-stage KM-LUAD.

In aged animals, it is found the abundance of CD103+ CD8+ T cells in the lung declines with age, accompanied by an accumulation of oxidative-damage-bearing AT2 cells. Collectively, the study establishes the vital function of CD103+ T cells in surveilling epithelial cells under oxidative stress to prevent malignancies, and unravels a potential immuno-dysregulation in the aged lung which contributes to tumorigenesis.

RP03707 effectively inhibits tumor cell growth in multiple KRASG12D cell lines. It also exhibits prolonged PK/PD effects and excellent efficacy in mouse CDX models bearing KRASG12D tumors, highlighting its potential for the treatment of KRASG12D-driven tumors in clinical settings.