期刊
CELL REPORTS
卷 27, 期 3, 页码 806-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.03.066
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资金
- Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]
- NIH-NCI Cancer Center Support grant [P30 CA008748]
- Swim Across America Laboratory
- Memorial Sloan Kettering Cancer Center, United States
- Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
- Department of Medicine, Memorial Sloan Kettering Cancer Center
- Weill Cornell Medicine, United States
- Ludwig Collaborative Laboratory
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.
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