دورية أكاديمية
The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.
| العنوان: | The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers. |
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| المؤلفون: | Saturno, G, Lopes, F, Niculescu-Duvaz, I, Niculescu-Duvaz, D, Zambon, A, Davies, L, Johnson, L, Preece, N, Lee, R, Viros, A, Holovanchuk, D, Pedersen, M, McLeary, R, Lorigan, P, Dhomen, N, Fisher, C, Banerji, U, Dean, E, Krebs, MG, Gore, M, Larkin, J, Marais, R, Springer, C |
| المساهمون: | Banerji, Udai |
| بيانات النشر: | ELSEVIER |
| سنة النشر: | 2020 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| الوصف: | BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; 278; application/pdf |
| اللغة: | English |
| تدمد: | 0923-7534 1569-8041 |
| العلاقة: | Annals of oncology : official journal of the European Society for Medical Oncology, 2021, 32 (2), pp. 269 - 278; https://repository.icr.ac.uk/handle/internal/4228Test |
| DOI: | 10.1016/j.annonc.2020.10.483 |
| الإتاحة: | https://doi.org/10.1016/j.annonc.2020.10.483Test https://repository.icr.ac.uk/handle/internal/4228Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.BCF39784 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 09237534 15698041 |
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| DOI: | 10.1016/j.annonc.2020.10.483 |