ABSTRACT
PURPOSE: Phosphatidylinositol 3-kinase (PI3K) inhibitors are being developed for the treatment of estrogen receptor α (ER)-positive breast cancer in combination with antiestrogens. Understanding the temporal response and pharmacodynamic effects of PI3K inhibition in ER(+) breast cancer will provide a rationale for treatment scheduling to maximize therapeutic index. EXPERIMENTAL DESIGN: Antiestrogen-sensitive and antiestrogen-resistant ER(+) human breast cancer cell lines and mice bearing PIK3CA-mutant xenografts were treated with the antiestrogen fulvestrant, the PI3K inhibitor GDC-0941 (pictilisib; varied doses/schedules that provided similar amounts of drug each week), or combinations. Cell viability, signaling pathway inhibition, proliferation, apoptosis, tumor volume, and GDC-0941 concentrations in plasma and tumors were temporally measured. RESULTS: Treatment with the combination of fulvestrant and GDC-0941, regardless of dose/schedule, was significantly more effective than that with single-agent treatments in fulvestrant-resistant tumors. Short-term, complete PI3K inhibition blocked cell growth in vitro more effectively than chronic, incomplete inhibition. Longer-term PI3K inhibition hypersensitized cells to growth factor signaling upon drug withdrawal. Different schedules of GDC-0941 elicited similar tumor responses. While weekly high-dose GDC-0941 with fulvestrant continuously suppressed PI3K signaling for 72 hours, inducing a bolus of apoptosis and inhibiting proliferation, PI3K reactivation upon GDC-0941 washout induced a proliferative burst. Fulvestrant with daily low-dose GDC-0941 metronomically suppressed PI3K for 6 to 9 hours/day, repeatedly inducing small amounts of apoptosis and temporarily inhibiting proliferation, followed by proliferative rebound compared with fulvestrant alone. CONCLUSIONS: Continuous and metronomic PI3K inhibition elicits robust anticancer effects in ER(+), PIK3CA-mutant breast cancer. Clinical exploration of alternate treatment schedules of PI3K inhibitors with antiestrogens is warranted. Clin Cancer Res; 22(9); 2250-60. ©2016 AACRSee related commentary by Toska and Baselga, p. 2099.
Subject(s)
Breast Neoplasms/drug therapy , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Class I Phosphatidylinositol 3-Kinases/genetics , Estrogen Receptor alpha/genetics , Mutation/genetics , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Receptor Modulators/pharmacology , Estrogen Receptor alpha/metabolism , Female , Fulvestrant , Humans , Indazoles/pharmacology , MCF-7 Cells , Mice , Mice, Inbred NOD , Mutation/drug effects , Signal Transduction/drug effects , Sulfonamides/pharmacology , Therapeutic IndexABSTRACT
BACKGROUND: Persistent chromosome segregation errors represent a conspicuous feature of human neoplasms. It is widely accepted that this chromosomal instability is associated with poor prognosis; however, its effect on therapeutic response is a matter of conjecture. METHODS: Here, the role of chromosome segregation errors in the response of patients with rectal adenocarcinoma to chemoradiation therapy (CRT) was examined. Pretreatment samples from 62 patients were surveyed for evidence of chromosome mis-segregation and mis-segregation frequency was correlated to the pathological response to CRT as determined by the tumor regression grade after surgical resection of irradiated tumors. RESULTS: Surprisingly, it was found that errors in chromosome segregation predicted enhanced pathological response of rectal adenocarcinoma to CRT (odds ratio, 3.9; P = .02). Furthermore, tumor response inversely correlated with the frequency of cells that exhibited segregation errors during anaphase (correlation coefficient, 0.94; P < .05). Strikingly, elevated chromosome mis-segregation combined with decreased levels of the DNA damage repair protein Mre11 portended a markedly enhanced response (odds ratio, 54.0; P = .008). CONCLUSIONS: The results of the current study demonstrate that chromosomal instability is a favorable predictor of response to CRT in patients with locally invasive rectal adenocarcinoma. Therefore, the authors propose that downstream structural damage to chromosomes resulting from segregation errors potentiates the effect of DNA-damaging therapies and synergizes with deficiencies in the DNA repair machinery. This work identifies a novel mechanistic marker that foretells treatment response to CRT and suggests that concomitant targeting of whole-chromosome segregation and DNA repair may constitute an effective therapeutic strategy.
