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 alpha-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylER alpha/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 alpha/Src and ER alpha/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 alpha+ and 3 ER alpha- PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ER alpha/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ER alpha/Src and ER alpha/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ER alpha+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ER alpha/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ER alpha signaling, since genomic degradation of ER alpha was unaltered in these tumors, whereas the treatment did not diminish the level of ER alpha/PI3K interaction. Interestingly, in 2 ER alpha- models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ER alpha/PI3K interaction. Conclusions Our results demonstrate that ER alpha/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ER alpha+ tumors was associated with a lack of impairment of ER alpha/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ER alpha/PI3K in ER alpha- tumors could constitute a promising therapeutic option.