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。
![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 - 天天要闻](https://cdn-dd.lujuba.top/img/loading.gif)
参考文献
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.
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.
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.
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.
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.
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.
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.
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.
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.
sattler, m., mohanty, a., kulkarni, p., and salgia, r. (2023). precision oncology provides opportunities for targeting kras-inhibitor resistance. trends cancer 9, 42–54.
akhave, n.s., biter, a.b., and hong, d.s. (2021). mechanisms of resistance to krasg12c-targeted therapy. cancer discov. 11, 1345–1352.
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.
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.
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.
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.
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.
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.
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.
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.
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
责编|探索君
排版|探索君
文章来源|“bioart”