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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 Review

Hyejin Choi

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

Jiehui Deng

New York University (NYU) - Division of Hematology and Medical Oncology

Shuai Li

New York University (NYU) - Division of Hematology and Medical Oncology

Elliott J. Brea

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

Tarik Silk

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

Jonathan Boiarsky

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

Esra A. Akbay

University of Texas at Dallas - Department of Pathology

Paul D. Smith

AstraZeneca Ltd

Taha Merghoub

Memorial Sloan Kettering Cancer Center - Department of Medicine

Kwok-Kin Wong

New York University (NYU) - Division of Hematology and Medical Oncology

Jedd D. Wolchok

Memorial Sloan Kettering Cancer Center - Department of Medicine

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Abstract

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.

Suggested Citation

Choi, Hyejin and Deng, Jiehui and Li, Shuai and Brea, Elliott J. and Silk, Tarik and Boiarsky, Jonathan and Akbay, Esra A. and Smith, Paul D. and Merghoub, Taha and Wong, Kwok-Kin and Wolchok, Jedd D., Pulsatile MEK Inhibition Improves Anti-Tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer (2018). Available at SSRN: https://ssrn.com/abstract=3224535 or http://dx.doi.org/10.2139/ssrn.3224535
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hyejin Choi

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

New York, NY 10065
United States

Jiehui Deng

New York University (NYU) - Division of Hematology and Medical Oncology

Bobst Library, E-resource Acquisitions
20 Cooper Square 3rd Floor
New York, NY 10003-711
United States

Shuai Li

New York University (NYU) - Division of Hematology and Medical Oncology

Bobst Library, E-resource Acquisitions
20 Cooper Square 3rd Floor
New York, NY 10003-711
United States

Elliott J. Brea

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

New York, NY 10065
United States

Tarik Silk

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

New York, NY 10065
United States

Jonathan Boiarsky

Memorial Sloan Kettering Cancer Center - Ludwig Collaborative and Swim Across America laboratory

New York, NY 10065
United States

Esra A. Akbay

University of Texas at Dallas - Department of Pathology

2601 North Floyd Road
Richardson, TX 75083
United States

Paul D. Smith

AstraZeneca Ltd

Cambridge
United Kingdom

Taha Merghoub (Contact Author)

Memorial Sloan Kettering Cancer Center - Department of Medicine

New York, NY 10065
United States

Kwok-Kin Wong

New York University (NYU) - Division of Hematology and Medical Oncology ( email )

Bobst Library, E-resource Acquisitions
20 Cooper Square 3rd Floor
New York, NY 10003-711
United States

Jedd D. Wolchok

Memorial Sloan Kettering Cancer Center - Department of Medicine

New York, NY 10065
United States