Cancer Cell｜任勝祥/周彩存/李飛/張喆/蔣濤合作提供KRAS G12D突變靶向治療新策略

分類：健康
瀏覽數：5347

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。


在這項研究中，作者團隊研發了一款高親和力、選擇性、長時效、非共價的kras g12d抑製劑，hrs-4642。體外，研究團隊首先通過spr實驗確認hrs-4642特異性結合kras g12d，其親和力為kras g12c的21倍，野生型kras蛋白的17倍。隨後通過結合抑制實驗，發現hrs-4642抑制kras g12d與sos1或raf1結合，發揮雙重阻滯作用，進而抑制下游mek-erk信號通路。在16個人源細胞系中，hrs-4642特異性抑制kras g12d突變細胞系增殖（ic50值為0.55-66.58 nm之間），而對其他kras突變亞型或野生型細胞系作用極弱（ic50值為248.50到大於10,000 nm）。體內，通過構建aspc-1、gp2d異種移植瘤模型及肺腺癌pdx模型，確認hrs-4642顯著抑制kras g12d腫瘤生長，且具有較好的葯代動力學（pk）、藥效學（pd）特徵，傾向於瘤內蓄積。在其i期臨床研究（nct05533463）中，hrs-4642也展示出臨床活性。2名接受過多線標準抗腫瘤治療的晚期非小細胞肺癌（nsclc）患者，分別接受200mg和300mg hrs-4642（每周一次）治療後，靶病灶分別縮小53%和31%，達部分緩解（pr）標準。這使得hrs-4642成為第一個被報道臨床有效的kras g12d特異性抑製劑。

研究團隊進一步通過體外全基因組crispr篩選，繪製了hrs-4642的增敏/耐受圖譜。對篩選數據進行富集分析，確定蛋白酶體或可為hrs-4642增敏靶標。對tcga數據進行分析也發現，蛋白酶體signature低表達與泛癌、肺腺癌及胰腺癌長生存相關。團隊進而通過體內外聯合給葯實驗，明確了hrs-4642聯合蛋白酶體抑製劑卡非佐米在體外協同殺傷kras g12d突變細胞系，體內聯合抑制kras g12d腫瘤生長。並通過rna-seq、dia蛋白質譜等手段，發現hrs-4642與卡非佐米聯合治療主要通過下調notch4信號通路及上調ifnα信號通路發揮協同抗腫瘤作用。

除了提供hrs-4642靶向及其聯合蛋白酶體抑製劑治療新策略，研究團隊通過流式細胞術、免疫組化等還發現，hrs-4642單葯或聯合卡非佐米可顯著促進kras g12d腫瘤中cd3+、cd4+、cd8+ t細胞的浸潤及激活，促進腫瘤免疫微環境（time）“炎化”，為kras g12d腫瘤靶免聯合提供了理論基礎。

模式圖（credit: cancer cell）


參考文獻

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    https://doi.org/10.1016/j.ccell.2024.06.001

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文章來源|“bioart”
“Cancer Cell｜任勝祥/周彩存/李飛/張喆/蔣濤合作提供KRAS G12D突變靶向治療新策略”相關視頻
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