YAP Mediates EGFR Inhibitor–Induced Dormancy in EGFR-Mutant Cancer

Tyrosine kinase inhibitors targeting EGFR are frequently initially effective in patients with EGFR-mutant non–small cell lung cancer (NSCLC), but relapse often occurs after a period of minimal residual disease. Some preclinical studies have suggested that, following treatment with an EGFR inhibitor, a population of drug-resistant, EGFR-mutant tumor cells are able to circumvent apoptosis by entering a state resembling dormancy. In EGFR-mutant human lung adenocarcinoma cells, Kurppa, Liu, and colleagues found that combination treatment with the EGFR inhibitor osimertinib and the MEK inhibitor trametinib resulted in cellular dormancy that was reversible following drug withdrawal. Interestingly, RNA-sequencing (RNA-seq) experiments demonstrated that cells in this dormant state exhibited a transcriptional profile remniscient of cellular senescence. Activation of the YAP–TEAD complex, part of the cancer-associated Hippo pathway, was necessary for dormancy following combination MEK and EGFR inhibition in vitro and in mouse xenograft experiments. Further, YAP–TEAD activation was required for viability of cancer cells treated with this drug combination, and in vivo single-cell RNA-seq experiments confirmed the existence of a high-YAP, senesecent-like state in residual cells that survived combined MEK- and EGFR-inhibitor treatment. Mechanistically, YAP activation appeared to help prevent EGFR inhibitor–triggered apoptosis by blocking induction of the gene encoding BCL2-modifying factor by complexing with SLUG (a transcription factor that acts on the gene encoding epithelial-to-mesenchymal transition protein) in EGFR-mutant NSCLC cells. In light of the finding that survival following combined MEK and EGFR inhibition was dependent on YAP, the authors constructed a novel TEAD inhibitor, which diminished the ability of EGFR-mutant cells to enter a dormant state. Although the safety and efficacy of such an inhibitor in patients remains to be established, these findings pave the way for further investigation of this pathway in EGFR-mutant tumors and provide insight into a possible mechanism by which relapse may occur in EGFR-mutant NSCLC treated with EGFR and MEK inhibitors.

Kurppa KJ, Liu Y, To C, Zhang T, Fan M, Vajdi A, et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 2020;37:104–22.E12.

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