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
  • 1. Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: [email protected].
  • 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: [email protected].
  • 10. Shanghai Hengrui Pharmaceutical Co., LTD, Shanghai 200433, China. Electronic address: [email protected].
  • 11. Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 12. Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China. Electronic address: [email protected].
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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