MEK inhibitor resistance in lung adenocarcinoma is associated with addiction to sustained ERK suppression

MEK inhibitors (MEKi) have limited efficacy in KRAS mutant lung adenocarcinoma (LUAD) patients, and this is attributed to both intrinsic and adaptive mechanisms of drug resistance. While many studies have focused on the former, there remains a dearth of data regarding acquired resistance to MEKi in LUAD. We established trametinib-resistant KRAS mutant LUAD cells through dose escalation and performed targeted MSK-IMPACT sequencing to identify drivers of MEKi resistance. Comparing resistant cells to their sensitive counterparts revealed alteration of genes associated with trametinib response. We describe a state of drug addiction in resistant cases where cells are dependent on continuous culture in trametinib for survival. We show that dependence on ERK2 suppression underlies this phenomenon and that trametinib removal hyperactivates ERK, resulting in ER stress and apoptosis. Amplification of KRAS(G12C) occurs in drug-addicted cells and blocking mutant-specific activity with AMG 510 rescues the lethality associated with trametinib withdrawal. Furthermore, we show that increased KRAS(G12C) expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study determines the drug-addicted phenotype in lung cancer is associated with KRAS amplification and demonstrates that toxic acquired genetic changes can develop de novo in the background of MAPK suppression with MEK inhibitors. 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.

Automated summary

MEK inhibitors have limited efficacy in KRAS mutant lung adenocarcinoma patients due to intrinsic and adaptive drug resistance mechanisms. Our study reveals a drug-addicted phenotype in trametinib-resistant KRAS mutant LUAD cells, dependent on continuous culture in trametinib for survival. We also identify KRAS amplification and hyperactive ERK signaling as toxic acquired genetic changes associated with drug addiction and suggest a drug holiday strategy for patients with mutant KRAS amplification.