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<p>The development of Kirsten rat sarcoma viral oncogene homologue (KRAS) targeted therapies has been the focus of cancer treatment. The most common mutant subtypes of KRAS driver genes are <i>G12C</i>, <i>G12V</i>, and <i>G12D</i>, and are associated with poor prognosis. Up to now, inhibitors specifically targeting KRAS<sup>G12D</sup> mutant proteins are all in the pre-clinical/early clinical research stage, and there is still a lack of effective clinical targeting strategies. In their recently published article, Zhou et al. developed a high-affinity, selective, long-acting, non-covalent KRAS<sup>G12D</sup>-specific inhibitor and, further combined with the proteasome inhibitor carfilzomib, found that this protocol can achieve the purpose of killing mutant cell lines and inhibiting tumor growth in vitro and in vivo. Here, we aim to describe a potential novel therapy for patients with KRAS<sup>G12D</sup> mutations and present the first KRAS<sup>G12D</sup>-specific inhibitor to be proven as clinically effective. Different mutations of KRAS gene and mechanisms of KRAS drug resistance were also discussed.</p>

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New exploration of KRASG12D inhibitors and the mechanisms of resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月17日

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  • Ying Li,
  • Junfeng Zhao,
  • Yintao Li

摘要

The development of Kirsten rat sarcoma viral oncogene homologue (KRAS) targeted therapies has been the focus of cancer treatment. The most common mutant subtypes of KRAS driver genes are G12C, G12V, and G12D, and are associated with poor prognosis. Up to now, inhibitors specifically targeting KRASG12D mutant proteins are all in the pre-clinical/early clinical research stage, and there is still a lack of effective clinical targeting strategies. In their recently published article, Zhou et al. developed a high-affinity, selective, long-acting, non-covalent KRASG12D-specific inhibitor and, further combined with the proteasome inhibitor carfilzomib, found that this protocol can achieve the purpose of killing mutant cell lines and inhibiting tumor growth in vitro and in vivo. Here, we aim to describe a potential novel therapy for patients with KRASG12D mutations and present the first KRASG12D-specific inhibitor to be proven as clinically effective. Different mutations of KRAS gene and mechanisms of KRAS drug resistance were also discussed.