Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.
Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.
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DOI：
10.1016/j.ccell.2014.11.006
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发表时间：
2015-01-12
期刊：
影响因子：
50.3
通讯作者：
Springer C
中科院分区：
文献类型：
--
作者：
Girotti MR;Lopes F;Preece N;Niculescu-Duvaz D;Zambon A;Davies L;Whittaker S;Saturno G;Viros A;Pedersen M;Suijkerbuijk BM;Menard D;McLeary R;Johnson L;Fish L;Ejiama S;Sanchez-Laorden B;Hohloch J;Carragher N;Macleod K;Ashton G;Marusiak AA;Fusi A;Brognard J;Frame M;Lorigan P;Marais R;Springer C
BRAF和MEK抑制剂在BRAF突变型黑色素瘤中有效，但大多数患者最终复发，获得性耐药，其他患者对这些药物存在内在耐药性。抗性通常由通过受体酪氨酸激酶（RTK）/SRC家族激酶（SFK）信号传导或突变的NRAS的途径再活化介导，其驱动途径的矛盾再活化。我们描述了也抑制SFK的泛RAF抑制剂（CCT 196969、CCT 241161）。这些化合物不驱动矛盾途径活化，并抑制BRAF和NRAS突变型黑色素瘤中的MEK/ERK。它们抑制对BRAF和BRAF/MEK抑制剂耐药的黑素瘤细胞和患者来源的异种移植物。因此，也抑制SFKs的矛盾打破泛RAF抑制剂可以为BRAF和NRAS突变型黑色素瘤提供一线治疗，并为产生耐药性的患者提供二线治疗。pan-RAF抑制剂也抑制SRC家族激酶该化合物在RAS突变细胞中不诱导ERK的反常激活该化合物在BRAF和NRAS突变黑素瘤中有活性该化合物在对BRAF或BRAF加MEK抑制剂有抗性的PDX中有活性Girotti等，描述了两种也抑制SRC家族激酶的泛RAF抑制剂。这些化合物不驱动矛盾的MEK/ERK活化，并且可以抑制NRAS突变细胞中的MEK。此外，所述药剂可以克服患者来源的异种移植物中对临床BRAF或组合BRAF/MEK抑制剂的抗性。
BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance. pan-RAF inhibitors also inhibit SRC family kinases The compounds do not induce paradoxical activation of ERK in RAS mutant cells The compounds are active in BRAF and NRAS mutant melanomas The compounds are active in PDXs resistant to BRAF or BRAF plus MEK inhibitors Girotti et al. describe two pan-RAF inhibitors that also inhibit SRC-family kinases. These compounds do not drive paradoxical MEK/ERK activation and can inhibit MEK in NRAS mutant cells. Moreover, the agents can overcome resistance to clinical BRAF or combination BRAF/MEK inhibitors in patient-derived xenografts.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
4.8
作者：
Vergani, Elisabetta;Vallacchi, Viviana;Rodolfo, Monica
通讯作者：
Rodolfo, Monica
影响因子：
28.2
作者：
Van Allen EM;Wagle N;Sucker A;Treacy DJ;Johannessen CM;Goetz EM;Place CS;Taylor-Weiner A;Whittaker S;Kryukov GV;Hodis E;Rosenberg M;McKenna A;Cibulskis K;Farlow D;Zimmer L;Hillen U;Gutzmer R;Goldinger SM;Ugurel S;Gogas HJ;Egberts F;Berking C;Trefzer U;Loquai C;Weide B;Hassel JC;Gabriel SB;Carter SL;Getz G;Garraway LA;Schadendorf D;Dermatologic Cooperative Oncology Group of Germany (DeCOG)
通讯作者：
Dermatologic Cooperative Oncology Group of Germany (DeCOG)
影响因子：
7.3
作者：
Menard, Delphine;Niculescu-Duvaz, Ion;Springer, Caroline J.
通讯作者：
Springer, Caroline J.
影响因子：
7
作者：
Turajlic, Samra;Furney, Simon J.;Marais, Richard
通讯作者：
Marais, Richard