Cancer Cell｜任胜祥/周彩存/李飞/张喆/蒋涛合作提供KRAS G12D突变靶向治疗新策略

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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。


在这项研究中，作者团队研发了一款高亲和力、选择性、长时效、非共价的kras g12d抑制剂，hrs-4642。体外，研究团队首先通过spr实验确认hrs-4642特异性结合kras g12d，其亲和力为kras g12c的21倍，野生型kras蛋白的17倍。随后通过结合抑制实验，发现hrs-4642抑制kras g12d与sos1或raf1结合，发挥双重阻滞作用，进而抑制下游mek-erk信号通路。在16个人源细胞系中，hrs-4642特异性抑制kras g12d突变细胞系增殖（ic50值为0.55-66.58 nm之间），而对其他kras突变亚型或野生型细胞系作用极弱（ic50值为248.50到大于10,000 nm）。体内，通过构建aspc-1、gp2d异种移植瘤模型及肺腺癌pdx模型，确认hrs-4642显著抑制kras g12d肿瘤生长，且具有较好的药代动力学（pk）、药效学（pd）特征，倾向于瘤内蓄积。在其i期临床研究（nct05533463）中，hrs-4642也展示出临床活性。2名接受过多线标准抗肿瘤治疗的晚期非小细胞肺癌（nsclc）患者，分别接受200mg和300mg hrs-4642（每周一次）治疗后，靶病灶分别缩小53%和31%，达部分缓解（pr）标准。这使得hrs-4642成为第一个被报道临床有效的kras g12d特异性抑制剂。

研究团队进一步通过体外全基因组crispr筛选，绘制了hrs-4642的增敏/耐受图谱。对筛选数据进行富集分析，确定蛋白酶体或可为hrs-4642增敏靶标。对tcga数据进行分析也发现，蛋白酶体signature低表达与泛癌、肺腺癌及胰腺癌长生存相关。团队进而通过体内外联合给药实验，明确了hrs-4642联合蛋白酶体抑制剂卡非佐米在体外协同杀伤kras g12d突变细胞系，体内联合抑制kras g12d肿瘤生长。并通过rna-seq、dia蛋白质谱等手段，发现hrs-4642与卡非佐米联合治疗主要通过下调notch4信号通路及上调ifnα信号通路发挥协同抗肿瘤作用。

除了提供hrs-4642靶向及其联合蛋白酶体抑制剂治疗新策略，研究团队通过流式细胞术、免疫组化等还发现，hrs-4642单药或联合卡非佐米可显著促进kras g12d肿瘤中cd3+、cd4+、cd8+ t细胞的浸润及激活，促进肿瘤免疫微环境（time）“炎化”，为kras g12d肿瘤靶免联合提供了理论基础。

模式图（credit: cancer cell）


参考文献

  1. zeissig, m.n., ashwood, l.m., kondrashova, o., and sutherland, k.d. (2023). next batter up! targeting cancers with kras-g12d mutations. trends cancer 9, 955–967.

  2. fell, j.b., fischer, j.p., baer, b.r., blake, j.f., bouhana, k., briere, d.m., brown, k.d., burgess, l.e., burns, a.c., burkard, m.r., et al. (2020). identification of the clinical development candidate mrtx849, a covalent krasg12c inhibitor for the treatment of cancer. j. med. chem. 63, 6679–6693.

  3. lanman, b.a., allen, j.r., allen, j.g., amegadzie, a.k., ashton, k.s., booker, s.k., chen, j.j., chen, n., frohn, m.j., goodman, g., et al. (2020). discovery of a covalent inhibitor of krasg12c (amg 510) for the treatment of solid tumors. j. med. chem. 63, 52–65.

  4. hallin, j., bowcut, v., calinisan, a., briere, d.m., hargis, l., engstrom, l.d., laguer, j., medwid, j., vanderpool, d., lifset, e., et al. (2022). anti-tumor efficacy of a potent and selective non-covalent krasg12d in- hibitor. nat. med. 28, 2171–2182.

  5. wang, x., allen, s., blake, j.f., bowcut, v., briere, d.m., calinisan, a., dahlke, j.r., fell, j.b., fischer, j.p., gunn, r.j., et al. (2022). identification of mrtx1133, a noncovalent, potent, and selective krasg12d inhibitor. j. med. chem. 65, 3123–3133.

  6. jiang, l., menard, m., weller, c., wang, z., burnett, l., aronchik, i., steele, s., flagella, m., zhao, r., evans, j.w.w., et al. (2023). abstract 526: rmc- 9805, a first-in-class, mutant-selective, covalent and oral krasg12d(on) inhibitor that induces apoptosis and drives tumor regression in preclinical models of krasg12d cancers. cancer res. 83, 526.

  7. mao, z., xiao, h., shen, p., yang, y., xue, j., yang, y., shang, y., zhang, l., li, x., zhang, y., et al. (2022). kras(g12d) can be targeted by potent inhibitors via formation of salt bridge. cell discov. 8, 5.

  8. kessler, d., gmachl, m., mantoulidis, a., martin, l.j., zoephel, a., mayer, m., gollner, a., covini, d., fischer, s., gerstberger, t., et al. (2019). drugging an undruggable pocket on kras. proc. natl. acad. sci. usa 116, 15823–15829.

  9. awad,m.m.,liu,s.,rybkin,i.i.,arbour,k.c.,dilly,j.,zhu,v.w.,johnson, m.l., heist, r.s., patil, t., riely, g.j., et al. (2021). acquired resistance to krasg12c inhibition in cancer. n. engl. j. med. 384, 2382–2393.

  10. sattler, m., mohanty, a., kulkarni, p., and salgia, r. (2023). precision oncology provides opportunities for targeting kras-inhibitor resistance. trends cancer 9, 42–54.

  11. akhave, n.s., biter, a.b., and hong, d.s. (2021). mechanisms of resistance to krasg12c-targeted therapy. cancer discov. 11, 1345–1352.

  12. zhu, c., guan, x., zhang, x., luan, x., song, z., cheng, x., zhang, w., and qin, j.-j. (2022). targeting kras mutant cancers: from druggable therapy to drug resistance. mol. cancer 21, 159.

  13. skoulidis, f., li, b.t., dy, g.k., price, t.j., falchook, g.s., wolf, j., italiano, a., schuler, m., borghaei, h., barlesi, f., et al. (2021). sotorasib for lung cancers with kras p.g12c mutation. n. engl. j. med. 384, 2371–2381.

  14. hong, d.s., fakih, m.g., strickler, j.h., desai, j., durm, g.a., shapiro, g.i., falchook, g.s., price, t.j., sacher, a., denlinger, c.s., et al. (2020). krasg12c inhibition with sotorasib in advanced solid tumors. n. engl. j. med. 383, 1207–1217.

  15. de langen, a.j., johnson, m.l., mazieres, j., dingemans, a.-m.c., mountzios, g., pless, m., wolf, j., schuler, m., lena, h., skoulidis, f., et al. (2023). sotorasib versus docetaxel for previously treated non- small-cell lung cancer with krasg12c mutation: a randomised, open-la- bel, phase 3 trial. lancet 401, 733–746.

  16. strickler, j.h., satake, h., george, t.j., yaeger, r., hollebecque, a., garrido-laguna, i., schuler, m., burns, t.f., coveler, a.l., falchook, g.s., et al. (2023). sotorasib in kras p.g12c-mutated advanced pancreatic cancer. n. engl. j. med. 388, 33–43.

  17. yaeger, r., weiss, j., pelster, m.s., spira, a.i., barve, m., ou, s.-h.i., leal, t.a., bekaii-saab, t.s., paweletz, c.p., heavey, g.a., et al. (2023). adagrasib with or without cetuximab in colorectal cancer with mutated kras g12c. n. engl. j. med. 388, 44–54.

  18. janne, p.a., riely, g.j., gadgeel, s.m., heist, r.s., ou, s.-h.i., pacheco, j.m., johnson, m.l., sabari, j.k., leventakos, k., yau, e., et al. (2022). adagrasib in non-small-cell lung cancer harboring a krasg12c mutation. n. engl. j. med. 387, 120–131.

  19. bekaii-saab, t.s., yaeger, r., spira, a.i., pelster, m.s., sabari, j.k., hafez, n., barve, m., velastegui, k., yan, x., shetty, a., et al. (2023). adagrasib in advanced solid tumors harboring a krasg12c mutation. j. clin. oncol. 41, 4097–4106.

  20. sacher, a., lorusso, p., patel, m.r., miller, w.h., garralda, e., forster, m.d., santoro, a., falcon, a., kim, t.w., paz-ares, l., et al. (2023). single-agent divarasib (gdc-6036) in solid tumors with a kras g12c mutation. n. engl. j. med. 389, 710–721.

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

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文章来源|“bioart”
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