引言
kras g12d是实体瘤中最常见kras突变亚型，在胰腺癌（pdac）和结直肠癌（crc）中排第1，在肺腺癌（luad）中排第2【1】。与kras g12c癌蛋白不同，kras g12d缺乏靠近switch-Ⅱ结合口袋的活性残基，使得开发共价抑制剂极具挑战性【1-3】。目前，一些研究团队基于不同策略研发了数个kras g12d抑制剂。例如，非共价抑制剂mrtx1133可结合switch-Ⅱ口袋，抑制kras g12d核苷酸交换及下游效应分子结合，从而发挥抗肿瘤效果【4,5】。其他抑制剂，如rmc-9805【6】、th-z835【7】及bi-2852【8】等也处于研究当中。然而，这些药物仍处于临床前/初步临床研究阶段，临床上kras g12d仍缺乏有效靶向策略。
此外，kras抑制剂面临的另一重大挑战为不可避免的耐受【9-12】。临床上，kras g12c抑制剂单药治疗客观有效率（orr）为7.1%-53.4%，中位无进展生存期（pfs）为4.0-13.1个月【13-20】，亟需联合治疗以增强疗效、增加获益人群。对此，yaeger【17】和hallin【4】等分别发现kras g12c和kras g12d抑制剂联合西妥昔单抗可增强疗效。这些研究充分说明寻找kras g12d抑制剂协同增敏靶标的重要性。
2024年6月27日，同济大学附属上海市肺科医院任胜祥、周彩存教授团队与复旦大学基础医学院李飞团队及恒瑞公司药物研发团队合作在cancer cell上发表题为anti-tumor efficacy of hrs-4642 and its potential combination with proteasome inhibition in kras g12d-mutant cancer的文章，提供了首个临床有效kras g12d特异性抑制剂——hrs-4642，及其与蛋白酶体抑制剂联合的治疗新策略。
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https://doi.org/10.1016/j.ccell.2024.06.001
责编|探索君
排版|探索君
文章来源|“bioart”
