MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression

Abstract

MEK inhibitors have yielded limited efficacy in KRAS-mutant lung adenocarcinoma (LUAD) patients due to drug resistance. We established trametinib-resistant KRAS-mutant LUAD cells and describe a state of “drug addiction” in a subset of resistant cases where cells are dependent on trametinib for survival. Dependence on ERK2 suppression underlies this phenomenon whereby trametinib removal hyperactivates ERK and results in ER stress and apoptosis. Amplification of KRASG12C occurs in drug-addicted cells and blocking mutant specific activity with AMG 510 rescues the lethality after trametinib withdrawal. Furthermore, increased KRASG12C expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study represents the first instance of this phenotype associated with KRAS amplification and demonstrates that acquired genetic changes that develop in the background of MAPK suppression can have unique consequence. We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a “drug holiday” to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.