MEK Mediation of Interferon Signaling in KRAS Mutant Lung Adenocarcinoma

Identification: Sisler, Daniel


Description

MEK Mediation of Interferon Signaling in KRAS Mutant Lung Adenocarcinoma
 
Dan Sisler, Natalia Gurule, Trista Hinz, Lindsay Marek, Bonnie Bullock, Howard Li, Raphael Nemenoff, Lynn Heasley
University of Colorado Denver, Anschutz Medical Campus, USA
 
Mutations in the KRAS oncogene are found in a large proportion of lung adenocarcinoma (LUAD). Unfortunately, unlike many oncogenic drivers, KRAS does not yet have a pharmacologically available inhibitor. Recently, immunotherapeutic options including immune checkpoint inhibitors have gained traction as durable and less toxic agents, and are now FDA approved for use in treating LUAD. A major caveat to this therapy is that less than 20% of patients demonstrate clinical response. Recent work has implicated the existence of an interferon (IFN) and T-cell inflamed gene signature in patient's tumors that respond to immunotherapy, suggesting that active IFN signaling and the presence of anti-tumor T-cells within the tumor microenvironment are necessary for response. Interestingly, we find that in addition to stalling proliferation, treating a KRAS mutant murine lung cancer cell line that fails to respond to checkpoint blockade, LLC, with MEK inhibitors (trametinib, selumetinib) induces robust transcription of IFN-stimulated genes (ISG) CXCL10, and MX2, while treating checkpoint sensitive CMT167s results in a similar induction of ISGs CXCL9 and MX2. Further data demonstrates 7 additional KRAS mutant murine lung cancer cell lines also undergo an induction of these same ISGs, albeit to varying degrees. Additionally, increases in STAT activation is seen upon MEK inhibition of LLCs, while downstream MAPK-regulated transcription factors such as c-Jun and PEA3-family ETS transcription factors such as ETV4 are downregulated, mirroring the effect of interferon treatment on these cells. Therefore, we propose that MAPK-regulated transcription factors functioning downstream of oncogenic KRAS and MEK may negatively regulate STAT activation, thus providing a mechanism of immune evasion. These results indicate that treating KRAS mutant tumors that fail to respond to immune checkpoint blockade with MEK inhibitors may sensitize these patient to anti-PD-1/PD-L1 therapy via relief from negative transcriptional regulators of JAK/STAT signaling.
 
Funding:
2016 Colorado Clinical and Translational Institute TL1 Awardee
2017 University of Colorado Lung, Head, and Neck Program T32 Awardee

Credits

Credits: None available.

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