YAP/TEAD involvement in resistance to paclitaxel chemotherapy in lung cancer

Abstract Background : The Yes-associated protein (YAP) oncoprotein has been linked to both metastasis and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/ TEA domain (TEAD) transcription factor interaction inhibitors, in chemo-resistant lung cancer cells. Methods : YAP subcellular localization, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC 50 ) of paclitaxel or trametinib, an inhibitor of Mitogen-Activated protein kinase and Erk Kinase (MEK), combined to YAP/TEAD inhibitor (IV#6) was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. Results : YAP activity was significantly higher in paclitaxel-resistant cell lines. YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib, in A549, K-Ras mutated cells, recaped synthetic lethality, sensitizing these cells (MEK) inhibition. The YAP/TEAD inhibitor lowered paclitaxel IC 50 in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increase of YAP/TEAD transcriptomic signature in resistant cells, down-regulated upon YAP inhibition. YAP/TEAD inhibitor enabled restoring paclitaxel sensitivity in A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Conclusions : Evidence on YAP/TEAD transcriptional program's role in resistance to chemotherapy opens routes towards therapeutic YAP targeting.