دورية أكاديمية
Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer
| العنوان: | Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer |
|---|---|
| المؤلفون: | Hyejin Choi, Jiehui Deng, Shuai Li, Tarik Silk, Lauren Dong, Elliott J. Brea, Sean Houghton, David Redmond, Hong Zhong, Jonathan Boiarsky, Esra A. Akbay, Paul D. Smith, Taha Merghoub, Kwok-Kin Wong, Jedd D. Wolchok |
| المصدر: | Cell Reports, Vol 27, Iss 3, Pp 806-819.e5 (2019) |
| بيانات النشر: | Elsevier, 2019. |
| سنة النشر: | 2019 |
| المجموعة: | LCC:Biology (General) |
| مصطلحات موضوعية: | Biology (General), QH301-705.5 |
| الوصف: | Summary: KRAS is one of the driver oncogenes in non-small-cell lung cancer (NSCLC) but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and enables their proliferation. Two MEKis, selumetinib and trametinib, induce T cell activation with increased CTLA-4 expression and, to a lesser extent, PD-1 expression on T cells in vivo after cyclical pulsatile MEKi treatment. In addition, the pulsatile dosing schedule alone shows superior anti-tumor effects and delays the emergence of drug resistance. Furthermore, pulsatile MEKi treatment combined with CTLA-4 blockade prolongs survival in mice bearing tumors with mutant Kras. Our results set the foundation and show the importance of a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy to optimally enhance tumor delay and promote long-term anti-tumor immunity. : KRAS mutant non-small-cell lung cancer (NSCLC) remains refractory to targeted therapeutics. Choi et al. show that pulsatile, rather than continuous, treatment with MEK inhibitors can maintain T cell activity better and prolong survival in mice with Kras mutant cancer. This effect is further enhanced when combined with CTLA-4 blockade. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2211-1247 45249075 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2211124719303961; https://doaj.org/toc/2211-1247 |
| DOI: | 10.1016/j.celrep.2019.03.066 |
| URL الوصول: | https://doaj.org/article/efa987c04f3a452490755f945bd7a287 |
| رقم الأكسشن: | edsdoj.fa987c04f3a452490755f945bd7a287 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 22111247 45249075 |
|---|---|
| DOI: | 10.1016/j.celrep.2019.03.066 |