VGLL1-directed TEAD activation drives endocrine therapy resistance in estrogen receptor positive breast cancer

Gemma, C.; Singh, A.; Belfiore, A.; Lai, C.; Periyasamy, M.; Abuelmaaty, S.; Davies, C.; Wang, X.; Simmons, G.; Nguyen, V.; Magnani, L.; Rakha, E.; Martin, L.-A.; Coombes, C.; Pruneri, G.; Buluwela, L.; Ali, S.

doi:10.1101/2020.11.29.402842

bioRxiv · 10.1101/2020.11.29.402842

VGLL1-directed TEAD activation drives endocrine therapy resistance in estrogen receptor positive breast cancer

Gemma, C.·Singh, A.·Belfiore, A.·Lai, C.·Periyasamy, M.·Abuelmaaty, S.·Davies, C.·Wang, X.·Simmons, G.·Nguyen, V.·Magnani, L.·Rakha, E.·Martin, L.-A.·Coombes, C.·Pruneri, G.·Buluwela, L.·Ali, S.

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Abstract

Resistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapsed patients1, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming provides possible routes to resistance2. By analysing histone H3 lysine 27 acetylation (H3K27ac) profiles in models of ET resistance, we discovered that selective ER down-regulators (SERDs) such as fulvestrant promote epigenetic activation of VGLL1, a co-activator for TEAD transcription factors. We show that VGLL1, acting via TEADs, promotes expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibits VGLL1/TEAD transcriptional programmes to block growth of the resistant cells and prevents growth. Among the VGLL1/TEAD-regulated genes, we identify EGFR, whereby VGLL1-directed EGFR upregulation sensitises fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, our findings identify VGLL1 as a transcriptional driver in ET resistance and advance new therapeutic possibilities for relapsed ER+ breast cancer patients.

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Gemma, C., Singh, A., Belfiore, A., Lai, C., Periyasamy, M., Abuelmaaty, S., Davies, C., Wang, X., Simmons, G., Nguyen, V., Magnani, L., Rakha, E., Martin, L.-A., Coombes, C., Pruneri, G., Buluwela, L., Ali, S.. 2020-11-29. VGLL1-directed TEAD activation drives endocrine therapy resistance in estrogen receptor positive breast cancer. https://doi.org/10.1101/2020.11.29.402842

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