Analysis of genomic and non-genomic signaling of estrogen receptor in PDX models of breast cancer treated with a combination of the PI3K inhibitor alpelisib (BYL719) and fulvestrant

BACKGROUND: Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ER-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER/Src/PI3K, a hallmark of aggressiveness and resistance to tamoxifen. We aimed to confirm the prognostic value of this complex and investigated whether its targeting could improve tumor response in vivo. METHODS: The interaction of ER/Src and ER/PI3K was studied by proximity ligation assay (PLA) in a cohort of 440 BC patients. We then treated patient-derived BC xenografts (PDXs) with fulvestrant or the PI3K inhibitor alpelisib (BYL719) alone or in combination. We analyzed their anti-proliferative effects on 6 ER+ and 3 ER PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. RESULTS: We confirmed that ER/Src and ER/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER signaling, since genomic degradation of ER was unaltered in these tumors, whereas the treatment did not diminish the level of ER/PI3K interaction. Interestingly, in 2 ER models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER/PI3K interaction. CONCLUSIONS: Our results demonstrate that ER/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER+ tumors was associated with a lack of impairment of ER/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER/PI3K in ER tumors could constitute a promising therapeutic option. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01433-8.