Open AccessA CRISPR screen identifies MAPK7 as a target for combination with MEK inhibition in KRAS mutant NSCLC
Author(s) -
Nicholas Dompe,
Christiaan Klijn,
Sara A. Watson,
Katherine R. Welker Leng,
Jenna Port,
Trinna Cuellar,
Colin Watanabe,
Benjamin Haley,
Richard M. Neve,
Marie Evangelista,
David Stokoe
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0199264
Subject(s) - kras , mek inhibitor , gene knockdown , mapk/erk pathway , mapk7 , cancer research , mutant , trametinib , crispr , biology , mutation , kinase , genetics , map kinase kinase kinase , cell culture , gene
Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies. In addition, we identified MAPK7 as a novel, strong hit and validated this finding using multiple orthogonal approaches including knockdown and pharmacological inhibition. We show that MAPK7 inhibition attenuates the re-activation of MAPK signaling occurring following long-term MEK inhibition, thereby illustrating that MAPK7 mediates pathway reactivation in the face of MEK inhibition. Finally, genetic knockdown of MAPK7 combined with the MEK inhibitor cobimetinib in a mutant KRAS NSCLC xenograft model to mediate improved tumor growth inhibition. These data highlight that MAPK7 represents a promising target for combination treatment with MEK inhibition in KRAS mutant NSCLC.