{"title":"New exploration of KRAS<sup>G12D</sup> inhibitors and the mechanisms of resistance.","authors":"Ying Li, Junfeng Zhao, Yintao Li","doi":"10.1186/s40164-025-00637-4","DOIUrl":null,"url":null,"abstract":"<p><p>The development of Kirsten rat sarcoma viral oncogene homologue (KRAS) targeted therapies has been the focus of cancer treatment. The most common mutant subtypes of KRAS driver genes are G12C, G12V, and G12D, and are associated with poor prognosis. Up to now, inhibitors specifically targeting KRAS<sup>G12D</sup> mutant proteins are all in the pre-clinical/early clinical research stage, and there is still a lack of effective clinical targeting strategies. In their recently published article, Zhou et al. developed a high-affinity, selective, long-acting, non-covalent KRAS<sup>G12D</sup>-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 KRAS<sup>G12D</sup> mutations and present the first KRAS<sup>G12D</sup>-specific inhibitor to be proven as clinically effective. Different mutations of KRAS gene and mechanisms of KRAS drug resistance were also discussed.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"39"},"PeriodicalIF":9.4000,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00637-4","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The development of Kirsten rat sarcoma viral oncogene homologue (KRAS) targeted therapies has been the focus of cancer treatment. The most common mutant subtypes of KRAS driver genes are G12C, G12V, and G12D, and are associated with poor prognosis. Up to now, inhibitors specifically targeting KRASG12D mutant proteins are all in the pre-clinical/early clinical research stage, and there is still a lack of effective clinical targeting strategies. In their recently published article, Zhou et al. 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.
期刊介绍：
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.
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