The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer

Abstract

Purpose Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and -resistant models of ER+ breast cancer. Methods Estrogen receptor-positive (ER+) breast cancer cells were treated +/− P7170. Fresh cores from primary ER+/HER2− tumors from two patients were treated +/− P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. Results In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤25 nM), and inhibited PI3K at higher concentrations (≥200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. Conclusions While P7170 inhibits PI3K and mTOR in ER+/HER2− human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.

Strategically Timing Inhibition of Phosphatidylinositol 3-Kinase to Maximize Therapeutic Index in Estrogen Receptor Alpha–Positive, PIK3CA-Mutant Breast Cancer

“…While we previously found that smaller MCF-7 tumors regress in response to fulv (38), larger tumors (500–1,000 mm 3 ) are generally unresponsive (Fig. S10 and Table S2).…”

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

“…This quinoline compounds demonstrated potent inhibition activity on mTORC1/mTORC2/ALK1, cell cycle arrest, induction of apoptosis, antiangiogenic activity. Moreover, it showed antitumor efficacy on both in vitro and in vivo studies against the erlotinib–sensitive and –insensitive models NSCLC and anti-estrogen models of ER+ breast cancer [ 86 , 87 , 88 ], reaching the clinical trials evaluation for patients with advanced refractory solid tumours ( number NCT01762410) [ 89 ].…”

HSP90 inhibitor AUY922 can reverse Fulvestrant induced feedback reaction in human breast cancer cells

“…Breast tumor samples were obtained after patients provided written informed consent for research use and the research was approved by the Ethics Committee of our institution. We performed this experiment according to Dr Jennifer R. Bean's paper . Untreated primary tumor samples from four patients with early‐stage ER+/HER2‐breast cancer were collected by using core needle biopsy, later confirmed by pathological examination.…”

“…We performed this experiment according to Dr Jennifer R. Bean's paper. (3) Untreated primary tumor samples from four patients with early-stage ER+/HER2-breast cancer were collected by using core needle biopsy, later confirmed by pathological examination. Within 1 h post-biopsy, samples were put into DMEM medium (Corning, NY, USA) with 10% fetal bovine serum (FBS) after several brief washes with 1XPBS, 100 nM Fulvestrant and 30 nM AUY922 was added in the medium for each single group and kept for 48 and 24 h, respectively.…”

“…Proteomic profiling also showed that LTED cells exhibit increased PI3K/AKT pathway activation. Other papers also showed that PI3K/AKT pathway has been activated in anti‐estrogen resistance in breast cancer, and chronic anti‐estrogen therapy induces the activation of the PI3K pathway in vitro, which might contribute to the cancer cell growth and proliferation. However, the EGFR inhibitor Gefitinib fails to alter the AKT reactivation …”