预约演示
更新于：2025-09-03
EGFR x KRAS G12D
更新于：2025-09-03
关联
NCT07020221
A Phase 1/2a, Open-label Study of VS-7375, a KRAS G12D (ON/OFF) Inhibitor, as Monotherapy and in Combination, in Patients With Advanced KRAS G12D-Mutated Solid Tumors
NCT06917079
A Phase 1a/1b Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of BBO-11818 in Subjects With Advanced KRAS Mutant Cancers
NCT06818812
A Phase 1, Open-Label, Multicenter Study of INCB186748 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation
100 项与 EGFR x KRAS G12D 相关的临床结果
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100 项与 EGFR x KRAS G12D 相关的转化医学
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2025-08-01Life Science Alliance
RalGAP complexes control secretion and primary cilia in pancreatic disease.
Article
作者: Pethő, Zoltán ; Ricker, Andrea ; Kümmel, Daniel ; Michalke, Esther ; Barz, Hannah ; Wardelmann, Eva ; Verma, Archana ; Oeckinghaus, Andrea ; Kerl, Kornelius ; Meisterernst, Michael ; Rasche, René ; Nüsse, Harald ; Apken, Lisa H ; Beel, Stephanie ; Steinestel, Konrad ; Klingauf, Jürgen
κB-Ras/RalGAP complexes limit the activity of Ral GTPases, which function in EGFR/Ras signaling. RalGAP expression is down-regulated in pancreatic cancer; however, the role of RalGAP and Ral GTPases in tumor development in vivo remained unclear. Here, we show that pancreatic RalGAPβ deficiency alone is sufficient to induce inflammation and neoplasia in vivo. We identify that this phenotype is triggered by disturbance of the secretory pathway and polarized exocytosis in acinar cells, demonstrating that RalGAP complexes uphold spatial control of Ral activity. We furthermore show that RALGAPβ deficiency results in defective primary cilium assembly, a process required for efficient acinar regeneration upon inflammation. Only primary cilium formation depends on κB-Ras proteins, suggesting that κB-Ras proteins are not essential for all RalGAP complex-controlled processes. 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.
2025-07-01LUNG CANCER
Clinicopathologic characteristics, co-mutation landscape, and survival outcomes of KRAS-G12D mutant lung adenocarcinoma in comparison to KRAS-G12C and EGFR-mutated subtypes
Article
作者: Armero, Victoria Saavedra ; Gaudreault, Nathalie ; Fiset, Pierre Oliver ; Kordahi, Manal ; Joubert, Philippe ; Orain, Michèle ; Lamaze, Fabien Claude ; Abolfathi, Hanie ; Gagné, Andréanne ; Bossé, Yohan ; Boudreau, Dominique K ; Desmeules, Patrice
Given the ongoing clinical development of KRASG12D specific inhibitors, we aimed to explore the clinicopathologic characteristics of KRASG12D mutant tumors. We analyzed 1,225 surgically resected LUAD from a large cohort of a French-Canadian cohort. Tumors were classified into five mutually exclusive molecular groups: KRASG12D (n = 82), KRASG12C (n = 311), KRASnon-G12C/G12D (n = 324), EGFR-mutant (n = 175), and WT (n = 333). Clinicopathological features, survival outcomes, and co-mutational profiles were compared across groups. KRASG12D tumors had the highest frequency of invasive mucinous adenocarcinoma (IMA) (17.1 %, p < 0.00001), spread through air spaces (STAS, p = 0.0001), lymphovascular invasion (LVI, p < 0.00001), and presentation at advanced stages compared to EGFR-mutant and other groups (p = 0.0031). TP53 was the most frequently co-mutated gene across all subgroups; however, it was significantly less frequent in KRASG12D tumors (47.8 %) compared to KRASG12C (68.1 %) and EGFR-mutant tumors (83.0 %) (p = 0.041). KRASG12D also exhibited a broader spectrum of low-frequency co-mutations, including BRAF (8.7 %) and GNAS (4.3 %). In the unstratified cohort, both KRASG12D and KRASG12C mutations were associated with significantly worse overall survival (OS) and recurrence-free survival (RFS) compared to EGFR-mutant tumors. In multivariable Cox models, KRASG12D remained independently associated with poorer OS (HR = 1.778, 95 % CI: 1.418-2.186, p = 0.021) and RFS (HR = 1.665, 95 % CI: 1.267-2.193, p = 0.045) when compared to EGFR. These associations were particularly evident in stage I disease. 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.
2025-06-01EUROPEAN JOURNAL OF PHARMACOLOGY
Small molecules for Kirsten rat sarcoma viral oncogene homolog mutant cancers: Past, present, and future
Review
作者: Han, Hua ; Wang, Mingtao ; Zheng, Xinyue ; Ni, Jiating ; Dong, Peiliang ; Yang, Meng
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been identified in more than 20% of human cancers as one of the most common oncogenes, especially in non-small cell lung, colorectal, and pancreatic cancers. KRAS regulates the activation of multiple proteins involved in cell growth and proliferation, such as extracellular regulated protein kinases and mammalian target of rapamycin, as a hub between the epidermal growth factor receptor (EGFR) and downstream MAPK and AKT pathways. However, due to the lack of a binding pocket, KRAS has long been considered an undruggable target in recent decades until the discovery of Sotorasib (AMG510). With the approval of Glecirasib (JAB-21822), there are three approved small molecule inhibitors of KRAS, all of which are KRAS G12C inhibitors. At the same time, the limited clinical benefits and rapid emergence of drug resistance to the approved inhibitors have also promoted the emergence of more therapeutics, such as tri-complexes and proteolysis-targeting chimeras (PROTAC). In this paper, we summarize the development of KRAS inhibitors (KRASG12C, KRASG12D, and KRASmulti inhibitors, PROTAC, and tri-complex) and discuss the challenges and opportunities in the discovery of KRAS inhibitors in the hope of providing insights into the development of novel medications for KRAS.
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