PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.
Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)-positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110alpha and p110beta, in ER(+) breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110alpha RNAi inhibited growth and promoted apoptosis in all tested ER(+) breast cancer cells under estrogen deprived-conditions, whereas p110beta RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110alpha/p110beta inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER(+) breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110alpha and p110beta catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER(+) breast cancer.
Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Robert J
RJ
Crowder
Chanpheng
C
Phommaly
Yu
Y
Tao
Jeremy
J
Hoog
Jingqin
J
Luo
Charles M
CM
Perou
Joel S
JS
Parker
Melinda A
MA
Miller
David G
DG
Huntsman
Li
L
Lin
Jacqueline
J
Snider
Sherri R
SR
Davies
John A
JA
Olson
Mark A
MA
Watson
Anthony
A
Saporita
Jason D
JD
Weber
Matthew J
MJ
Ellis
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004958:Estradiol / Q000494:pharmacology*; D005784:Gene Amplification; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017404:In Situ Hybridization, Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000096:biosynthesis; D014162:Transfection
D058534:Class I Phosphatidylinositol 3-Kinases; D004958:Estradiol; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human; C531198:dactolisib