Pulsatile MEK Inhibition Improves Anti-Tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer
44 Pages Posted: 1 Aug 2018 Sneak Peek Status: Under ReviewMore...
KRAS is one of the most commonly identified driver oncogenes with well-characterized mutations in non-small cell lung cancer (NSCLC) but remains refractory to currently available modalities of targeted pathway inhibition. One promising therapeutic strategy has been to circumvent KRAS activation by inhibiting its downstream kinase MEK. However, despite temporarily slowing tumor growth, MEK inhibition results in a subsequent dramatic rebound of tumor development. Recently, immunologic checkpoint blockade has shown therapeutic promise by potentiating suppressed effector T cells in the tumor microenvironment. Therefore, to investigate more effective therapies for the treatment for KRAS mutant NSCLC, we studied the impact of MEK inhibition on the immune microenvironment to systematically optimize a combinational treatment approach. Here we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) activates T cells and enables their proliferation. Both selumetinib and trametinib, two common clinically used MEKis, induced T cell activation with increased CTLA-4 expression and to a lesser extent, PD-1 expression on T cells in vivo after cyclical pulsatile MEKis treatment compared to continuous treatment. In addition, the pulsatile dosing schedule alone showed superior anti-tumor effects and delayed the emergence of drug resistance. Furthermore, pulsatile MEKis treatment when combined with CTLA-4 blockade prolonged survival in mice bearing tumors with Kras mutations. Current therapies are mainly based on continuous administration of targeted drugs. 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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