Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer.

Authors:
Hyejin Choi
Hyejin Choi
Weill Cornell Medical College of Cornell University
United States
Jiehui Deng
Jiehui Deng
Beckman Research Institute
United States
Shuai Li
Shuai Li
Mayo Clinic Rochester
Manager/senior postdoc
Rochester, MN | United States
Tarik Silk
Tarik Silk
Memorial Sloan Kettering Cancer Center
Lauren Dong
Lauren Dong
Memorial Sloan Kettering Cancer Center
Elliott J Brea
Elliott J Brea
Sloan-Kettering Institute
David Redmond
David Redmond
Institute for Computational Biomedicine

Cell Rep 2019 Apr;27(3):806-819.e5

Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

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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Source
https://linkinghub.elsevier.com/retrieve/pii/S22111247193039
Publisher Site
http://dx.doi.org/10.1016/j.celrep.2019.03.066DOI Listing
April 2019
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