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

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Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer
Cancer Cell ( IF 48.8 ) Pub Date : 2024-06-27 , DOI: 10.1016/j.ccell.2024.06.001
Caicun Zhou ₁ , Chongyang Li ₂ , Libo Luo ₁ , Xin Li ₃ , Keyi Jia ₁ , Ning He ₃ , Shiqi Mao ₁ , Wanying Wang ₁ , Chuchu Shao ₁ , Xinyu Liu ₁ , Kan Huang ₄ , Yaxin Yu ₅ , Xinlei Cai ₆ , Yingxue Chen ₅ , Zican Dai ₅ , Wei Li ₁ , Jia Yu ₁ , Jiayu Li ₁ , Feng Shen ₃ , Zaiyong Wang ₃ , Feng He ₃ , Xing Sun ₃ , Rongfu Mao ₃ , Wei Shi ₃ , Jun Zhang ₇ , Tao Jiang ₁ , Zhe Zhang ₃ , Fei Li ₅ , Shengxiang Ren ₁

Affiliation

Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China.
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.
Shanghai Hengrui Pharmaceutical Co., LTD, Shanghai 200433, China.
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.
Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
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.
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.

is the most frequently mutated oncogenic 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 -mutant cancers both and . 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 -mutant cancers, for whom effective treatments are currently lacking.

中文翻译：

HRS-4642 的抗肿瘤功效及其与 KRAS G12D 突变型癌症中蛋白酶体抑制的潜在组合

是实体瘤中最常见突变的致癌亚型，并且在临床环境中仍然无法用药物治疗。在这里，我们开发了一种高亲和力、选择性、长效、非共价 KRAS G12D 抑制剂 HRS-4642，其亲和常数为 0.083 nM。 HRS-4642 对和突变型癌症均表现出强大的功效。重要的是，在一项 1 期临床试验中，HRS-4642 在剂量递增的队列中表现出有希望的抗肿瘤活性。此外，通过全基因组 CRISPR-Cas9 筛选破译了 HRS-4642 的致敏和耐药谱，揭示了蛋白酶体作为致敏靶标。我们进一步观察到蛋白酶体抑制剂卡非佐米提高了HRS-4642的抗肿瘤功效。此外，HRS-4642无论作为单一药物还是与卡非佐米联合使用，都能将肿瘤微环境重塑为免疫允许的环境。总之，这项研究为目前缺乏有效治疗的突变癌症患者提供了潜在的治疗方法。

更新日期：2024-06-27

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