同济大学任胜祥等研究人员合作发现，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。相关论文于2024年6月27日在线发表在《癌细胞》杂志上。

研究人员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，研究人员还通过全基因组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。

研究人员进一步观察到，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，使其趋向于免疫许可型。总之，这项研究为目前尚缺乏有效治疗方法的KRAS G12D突变癌症患者提供了潜在的治疗方法。

据悉，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。

附：英文原文

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

Author: 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, Feng He, Xing Sun, Rongfu Mao, Wei Shi, Jun Zhang, Tao Jiang, Zhe Zhang, Fei Li, Shengxiang Ren

Issue&Volume: 2024-06-27

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 againstKRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumoractivity in the escalating dosing cohorts. Furthermore, the sensitization and resistancespectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, whichunveiled proteasome as a sensitization target. We further observed that the proteasomeinhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally,HRS-4642, either as a single agent or in combination with carfilzomib, reshaped thetumor microenvironment toward an immune-permissive one. In summary, this study providespotential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

DOI: 10.1016/j.ccell.2024.06.001

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00226-5