The receptor tyrosine kinase EphA2 promotes glutamine metabolism in tumors by activating the transcriptional coactivators YAP and TAZ

By activating the transcription cofactors YAP and TAZ, the receptor EphA2 mediates a metabolic switch to glutamine dependency in HER2+ breast cancers. EphA2 exposes an Achilles’ heel in breast cancer Cancer cells alter their metabolism to adapt to the tumor microenvironment, for example, by switching from a reliance on glucose to glutamine. Edwards et al. found that a high abundance of the receptor tyrosine kinase EphA2 drives a switch to glutamine dependency in HER2-positive breast cancers. In cells and mouse models, EphA2 activated Rho-ROCK signaling that mediated the nuclear accumulation of the transcriptional coactivators YAP and TAZ, where they induced the expression of genes encoding an amino acid transporter that promoted glutamine uptake and an enzyme that promoted glutamine metabolism. EphA2 may be a biomarker for sensitivity to glutaminase inhibitors in patient tumors. However, because inhibiting glutamine metabolism may have adverse effects elsewhere, such as in the immune system, inhibiting EphA2 signaling upstream of YAP and TAZ may be a way to exploit the glutamine dependency of HER2-positive breast cancers. Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Glutamine transporters and glutaminase activity are critical for glutamine metabolism in tumor cells. We found that the receptor tyrosine kinase EphA2 activated the TEAD family transcriptional coactivators YAP and TAZ (YAP/TAZ), likely in a ligand-independent manner, to promote glutamine metabolism in cells and mouse models of HER2-positive breast cancer. Overexpression of EphA2 induced the nuclear accumulation of YAP and TAZ and increased the expression of YAP/TAZ target genes. Inhibition of the GTPase Rho or the kinase ROCK abolished EphA2-dependent YAP/TAZ nuclear localization. Silencing YAP or TAZ substantially reduced the amount of intracellular glutamate through decreased expression of SLC1A5 and GLS, respectively, genes that encode proteins that promote glutamine uptake and metabolism. The regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In patient breast cancer tissues, EphA2 expression positively correlated with that of YAP and TAZ, as well as that of GLS and SLC1A5. Although high expression of EphA2 predicted enhanced metastatic potential and poor patient survival, it also rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. The findings define a previously unknown mechanism of EphA2-mediated glutaminolysis through YAP/TAZ activation in HER2-positive breast cancer and identify potential therapeutic targets in patients.