Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer

IF 48.8 1区 医学 Q1 CELL BIOLOGY
Caicun Zhou, Chongyang Li, Libo Luo, Xin Li, Keyi Jia, Ning He, Shiqi Mao, Wanying Wang, Chuchu Shao, Xinyu Liu, Kan Huang, Yaxin Yu, Xinlei Cai, Yingxue Chen, Zican Dai, Wei Li, Jia Yu, Jiayu Li, Feng Shen, Zaiyong Wang, Shengxiang Ren
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引用次数: 0

Abstract

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

Abstract Image

HRS-4642 的抗肿瘤疗效及其与蛋白酶体抑制剂联合治疗 KRAS G12D 突变癌症的潜力
KRAS G12D 是实体瘤中最常发生突变的致癌 KRAS 亚型,但在临床上仍无法治疗。在这里,我们开发了一种高亲和性、选择性、长效和非共价的 KRAS G12D 抑制剂 HRS-4642,其亲和力常数为 0.083 nM。HRS-4642 在体外和体内对 KRAS G12D 突变癌症均有显著疗效。重要的是,在 1 期临床试验中,HRS-4642 在剂量递增的组群中表现出良好的抗肿瘤活性。此外,我们还通过全基因组 CRISPR-Cas9 筛选破解了 HRS-4642 的增敏和耐药谱,发现蛋白酶体是增敏靶点。我们进一步观察到,蛋白酶体抑制剂卡非佐米提高了HRS-4642的抗肿瘤疗效。此外,HRS-4642 无论是作为单药还是与卡非佐米联合使用,都能重塑肿瘤微环境,使其趋向于免疫容许型。总之,这项研究为KRAS G12D突变癌症患者提供了潜在的治疗方法,目前尚缺乏有效的治疗方法。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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