2. Academic Validation
  3. Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer

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

  • Cancer Cell. 2024 Jul 8;42(7):1286-1300.e8. doi: 10.1016/j.ccell.2024.06.001.
Caicun Zhou 1,  Chongyang Li 2,  Libo Luo 3,  Xin Li 4,  Keyi Jia 3,  Ning He 4,  Shiqi Mao 3,  Wanying Wang 3,  Chuchu Shao 3,  Xinyu Liu 3,  Kan Huang 5,  Yaxin Yu 6,  Xinlei Cai 7,  Yingxue Chen 6,  Zican Dai 6,  Wei Li 3,  Jia Yu 3,  Jiayu Li 3,  Feng Shen 4,  Zaiyong Wang 4,  Feng He 4,  Xing Sun 4,  Rongfu Mao 4,  Wei Shi 4,  Jun Zhang 8,  Tao Jiang 9,  Zhe Zhang 10,  Fei Li 11,  Shengxiang Ren 12
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: caicunzhou_dr@163.com.
  • 2 Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 3 Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
  • 4 Shanghai Hengrui Pharmaceutical Co., LTD, Shanghai 200433, China.
  • 5 Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
  • 6 Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 7 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 100049, China.
  • 8 Division of Medical Oncology, Department of Internal Medicine; Department of Cancer Biology, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA.
  • 9 Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: tonyjiangdr@163.com.
  • 10 Shanghai Hengrui Pharmaceutical Co., LTD, Shanghai 200433, China. Electronic address: zhe.zhang.zz1@hengrui.com.
  • 11 Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: li_fei@fudan.edu.cn.
  • 12 Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: harry_ren@tongji.edu.cn.
PMID: 38942026 DOI: 10.1016/j.ccell.2024.06.001
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.

Keywords

HRS-4642; KRAS G12D; carfilzomib; tumor immune microenvironment.

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