引言
kras g12d是實體瘤中最常見kras突變亞型，在胰腺癌（pdac）和結直腸癌（crc）中排第1，在肺腺癌（luad）中排第2【1】。與kras g12c癌蛋白不同，kras g12d缺乏靠近switch-Ⅱ結合口袋的活性殘基，使得開發共價抑製劑極具挑戰性【1-3】。目前，一些研究團隊基於不同策略研發了數個kras g12d抑製劑。例如，非共價抑製劑mrtx1133可結合switch-Ⅱ口袋，抑制kras g12d核苷酸交換及下游效應分子結合，從而發揮抗腫瘤效果【4,5】。其他抑製劑，如rmc-9805【6】、th-z835【7】及bi-2852【8】等也處於研究當中。然而，這些藥物仍處於臨床前/初步臨床研究階段，臨床上kras g12d仍缺乏有效靶向策略。
此外，kras抑製劑面臨的另一重大挑戰為不可避免的耐受【9-12】。臨床上，kras g12c抑製劑單葯治療客觀有效率（orr）為7.1%-53.4%，中位無進展生存期（pfs）為4.0-13.1個月【13-20】，亟需聯合治療以增強療效、增加獲益人群。對此，yaeger【17】和hallin【4】等分別發現kras g12c和kras g12d抑製劑聯合西妥昔單抗可增強療效。這些研究充分說明尋找kras g12d抑製劑協同增敏靶標的重要性。
2024年6月27日，同濟大學附屬上海市肺科醫院任勝祥、周彩存教授團隊與復旦大學基礎醫學院李飛團隊及恆瑞公司藥物研發團隊合作在cancer cell上發表題為anti-tumor efficacy of hrs-4642 and its potential combination with proteasome inhibition in kras g12d-mutant cancer的文章，提供了首個臨床有效kras g12d特異性抑製劑——hrs-4642，及其與蛋白酶體抑製劑聯合的治療新策略。
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https://doi.org/10.1016/j.ccell.2024.06.001
責編|探索君
排版|探索君
文章來源|「bioart」
