2. Academic Validation
  3. Site-specific mutagenesis screening in KRASG12D mutant library to uncover resistance mechanisms to KRASG12D inhibitors

Site-specific mutagenesis screening in KRASG12D mutant library to uncover resistance mechanisms to KRASG12D inhibitors

  • Cancer Lett. 2024 Jun 1:591:216904. doi: 10.1016/j.canlet.2024.216904.
Jeesoo Choi 1,  Ju-Young Shin 2,  Taeyul K Kim 1,  Kiwook Kim 2,  Jiyun Kim 2,  Eunhye Jeon 3,  Juyeong Park 4,  Yoon Dae Han 5,  Kyung-A Kim 1,  Taebo Sim 6,  Hui Kwon Kim 7,  Han Sang Kim 8
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
  • 2 Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
  • 3 Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
  • 4 Department of Medicine, Graduate School, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Theragen Bio Co., Ltd, Seongnam-si, 13488, Republic of Korea.
  • 5 Department of Surgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
  • 6 Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.
  • 7 Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: huikwonkim@skku.edu.
  • 8 Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. Electronic address: modeerfhs@yuhs.ac.
PMID: 38642608 DOI: 10.1016/j.canlet.2024.216904
Abstract

KRAS plays a crucial role in regulating cell survival and proliferation and is one of the most commonly mutated oncogenes in human cancers. The novel KRASG12D inhibitor, MRTX1133, demonstrates promising antitumor efficacy in vitro and in vivo. However, the development of acquired resistance in treated patients presents a considerable challenge to sustained therapeutic effectiveness. In response to this challenge, we conducted site-specific mutagenesis screening to identify potential secondary mutations that could induce resistance to MRTX1133. We screened a range of KRASG12D variants harboring potential secondary mutations, and 44 representative variants were selected for in-depth validation of the pooled screening outcomes. We identified eight variants (G12D with V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L) that exhibited substantial resistance, with V9W showing notable resistance, and downstream signaling analyses and structural modeling were conducted. We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human Cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

Keywords

Drug resistance; KRAS inhibitor; Site-specific mutagenesis screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-134813
    99.97%, KRAS G12D抑制剂
    Ras
  • HY-153724
    99.65%, 泛-KRAS抑制剂
    Ras
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