Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in murine Kras mutant lung cancer Journal Article


Authors: Choi, H.; Deng, J.; Li, S.; Silk, T.; Dong, L.; Brea, E. J.; Houghton, S.; Redmond, D.; Zhong, H.; Boiarsky, J.; Akbay, E. A.; Smith, P. D.; Merghoub, T.; Wong, K. K.; Wolchok, J. D.
Article Title: Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in murine Kras mutant lung cancer
Abstract: 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. © 2019 The Authors 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. © 2019 The Authors
Journal Title: Cell Reports
Volume: 27
Issue: 3
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2019-01-01
Start Page: 806
End Page: 819.e5
Language: English
DOI: 10.1016/j.celrep.2019.03.066
PROVIDER: scopus
PUBMED: 30995478
PMCID: PMC6719696
DOI/URL:
Notes: Article -- Export Date: 1 May 2019 -- Source: Scopus
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MSK Authors
  1. Jedd D Wolchok
    905 Wolchok
  2. Taha Merghoub
    365 Merghoub
  3. Hong Zhong
    35 Zhong
  4. Tarik Christopher Silk
    10 Silk
  5. Lauren   Dong
    15 Dong
  6. Elliott Joseph Brea
    17 Brea
  7. Hyejin Choi
    8 Choi