High efficacy of combined MEK Inhibitor Trametinib and RTK Inhibitor Anlotinib Therapy in KRAS-Mutant Lung Cancer

Oncogenic KRAS mutations frequently detected in non-small cell lung cancer (NSCLC)1,2, have been considered undruggable until recent development of inhibitors, e.g., sortorasib, adagrasib or divarasib, specifically targeting KRASG12C 3-6. However, it still remains as a big challenge to target all the KRAS mutants besides KRASG12C 2,7,8. We here found that MEK inhibitor trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) in NSCLC, and combined treatments with trametinib and anlotinib, a pan-RTK inhibitor, effectively inhibited KRAS-mutant lung cancer progression. Overall design: KRAS-mutant NSCLC cells were treated with trametinib (10nM) for 2, 5, and 10 days in 6-well plates. 4 KRAS-mutant NSCLC cell lines (A549, Calu-1, H460 and H23) were used in trametinib adaptive resistance analysis. 3 samples for each timepoint were collected for sequencing and bioinformatic analysis. For the combinational analysis, A549 cells were treated with trametinib (10nM) or anlotinib (1µM) or combination treatments for 24 hours in 6-well plates. 3 samples for each treatment were collected for sequencing and bioinformatic analysis.