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

Breast Cancer Research

Loay Kassem¹  Sophie Vacher²  Ivan Bièche²  Ludivine Morisset³  Ludmilla De Plater³  Rania El Botty³  Elisabetta Marangoni³  Ahmed Dahmani³  Laura Sourd³  Elodie Montaudon³  Muriel Le Romancer⁴  Olivier Trédan⁴  Julien Jacquemetton⁴  Coralie Poulard⁴  Isabelle Treilleux⁴  Sophie Chateau-Joubert⁵ 

[1] Clinical Oncology Department, Faculty of Medicine, Cairo University;Genetics Department, Institut Curie;Translational Research Department, Institut Curie, PSL University;Université de Lyon;École Nationale Vétérinaire d’Alfort, BioPôle Alfort;

关键词: Breast cancer;    Estrogen signaling;    Resistance;    PI3K;    PDX;    Biomarker;   

DOI  :  10.1186/s13058-021-01433-8

来源: DOAJ

【 摘 要 】

Abstract Background Endocrine therapies targeting estrogen signaling have significantly improved breast cancer (BC) patient survival, although 40% of ERα-positive BCs do not respond to those therapies. Aside from genomic signaling, estrogen triggers non-genomic pathways by forming a complex containing methylERα/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 ERα/Src and ERα/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 ERα+ and 3 ERα− PDX models. Genomic and non-genomic estrogen signaling were assessed by measuring ERα/PI3K interaction by PLA and the expression of estrogen target genes by RT-QPCR, respectively. Results We confirmed that ERα/Src and ERα/PI3K interactions were associated with a trend to poorer survival, the latter displaying the most significant effects. In ERα+ tumors, the combination of BYL719 and fulvestrant was more effective than fulvestrant alone in 3 models, irrespective of PI3K, PTEN status, or ERα/PI3K targeting. Remarkably, resistance to fulvestrant was associated with non-genomic ERα signaling, since genomic degradation of ERα was unaltered in these tumors, whereas the treatment did not diminish the level of ERα/PI3K interaction. Interestingly, in 2 ERα− models, fulvestrant alone impacted tumor growth, and this was associated with a decrease in ERα/PI3K interaction. Conclusions Our results demonstrate that ERα/PI3K may constitute a new prognostic marker, as well as a new target in BC. Indeed, resistance to fulvestrant in ERα+ tumors was associated with a lack of impairment of ERα/PI3K interaction in the cytoplasm. In addition, an efficient targeting of ERα/PI3K in ERα− tumors could constitute a promising therapeutic option.

【 授权许可】

Unknown