ELMO2 is a therapeutic vulnerability in mesenchymal-like and drug-resistant non-small cell lung cancer.

Epithelial-mesenchymal transition drives tumor metastasis and therapeutic resistance, yet few treatments have been developed that target this process. Here, we show that ELMO2 represents a specific vulnerability in mesenchymal-like cells. ELMO2 suppression induces excessive autophagy and cell death via FAK activity inhibition. We identify ELMO3 as a functional paralog that compensates for ELMO2 loss, establishing a synthetic lethal interaction. The epithelial-mesenchymal transition core regulator ZEB1 represses ELMO3 transcription in mesenchymal-like cells, rendering them sensitive to ELMO2 blockade. ELMO3 is significantly downregulated in epithelial-mesenchymal transition-associated EGFR inhibitor-resistant cells. Furthermore, the survival of these resistant, mesenchymal-like cells depends on ELMO2/FAK signaling. Through structure-based screening, we identify C52, a small-molecule ELMO2 inhibitor that effectively kills ELMO3-low lung cancer cells and EGFR inhibitor-resistant cells. Our study uncovers an ELMO2-ELMO3 synthetic lethal interaction and establishes ELMO2 as a potential therapeutic target for mesenchymal-like cancer and drug-resistant non-small cell lung cancer.