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Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.

ABSTRACT: Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using in vitro and in vivo breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation. Moreover, abemaciclib exposure led to durable inhibition of pRb, TopoII? expression and DNA synthesis, which were maintained after drug removal. Treatment of ER+ breast cancer cells also led to a senescence response as indicated by accumulation of ?-galactosidase, formation of senescence-associated heterochromatin foci, and a decrease in FOXM1 positive cells. Continuous exposure to abemaciclib altered breast cancer cell metabolism and induced apoptosis. In a xenograft model of ER+ breast cancer, abemaciclib monotherapy caused regression of tumor growth. Overall these data indicate that abemaciclib is a CDK4 and CDK6 inhibitor that, as a single agent, blocks breast cancer cell progression, and upon longer treatment can lead to sustained antitumor effects through the induction of senescence, apoptosis, and alteration of cellular metabolism.

SUBMITTER: Torres-Guzman R

PROVIDER: S-EPMC5642494 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.

Torres-Guzmán Raquel R Calsina Bruna B Hermoso Ana A Baquero Carmen C Alvarez Beatriz B Amat Joaquín J McNulty Ann M AM Gong Xueqian X Boehnke Karsten K Du Jian J de Dios Alfonso A Beckmann Richard P RP Buchanan Sean S Lallena María José MJ

Oncotarget 20170510 41

Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using <i>in vitro</i> and <i>in vivo</i> breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, ...[more]

PMID: 29050219

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Project description:BackgroundCyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.Patients and methodsWomen ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.ResultsSixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.ConclusionsAbemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT02057133.

Project description:BackgroundAKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited.MethodsIn a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed.ResultsOverall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.ConclusionsCapivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.).

Project description:PurposeInhibition of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) pathway exerts a considerable inhibitory effect, preventing the spread and metastasis of breast cancer cells and promoting tumor regression. In this study, we examined the antitumor activity of TQB3616, a novel inhibitor of CDK4/6 activity, which showed a greater efficacy improvement in antitumor effects.MethodsTQB3616 group, abemaciclib group and endocrine or HER-2 targeted combination therapy group were set up respectively. The effects of drugs on cell proliferation activity, cell cycle, apoptosis, downstream protein expression and gene expression of HR positive (T47D, MCF-7) and HER-2 positive (BT474, MDA-MB-361) breast cancer cell lines were studied. The antiproliferative effect of TQB3616 was also measured in vivo.ResultsTQB3616 showed a remarkable inhibitory effect on the proliferation of hormone receptor-positive breast cancer cells in vitro. In addition, TQB3616 combined with endocrine therapy or Human Epidermal Growth Factor Receptor 2 (HER2) targeted therapy showed significant synergistic antitumor activity in estrogen receptor (ER)-positive/HER2-negative or HER2-positive breast cancer. In contrast to abemaciclib, which targets the CDK4/6 pathway with proven efficacy, the oral agent TQB3616 not only induced G1 stalling, leading to a profound reduction in the level of RB protein phosphorylated at Ser807/811, but also showed enhanced tumor killing effects by promoting cell apoptosis. Oral administration of TQB3616 showed more potent antitumor activity than abemaciclib in an in vitro breast cancer xenograft model, causing significant tumor regression associated with sustained target inhibition in tumor tissue and manageable in vivo toxicity.ConclusionThe results of this study indicate that TQB3616 is a novel CDK4/6 inhibitor, and its highly effective antitumor activity against breast cancer is expected to yield promising therapeutic effects in clinical studies.

Project description:BACKGROUND:In the phase III MONARCH 2 study (NCT02107703), abemaciclib plus fulvestrant significantly improved progression-free survival (PFS) versus placebo plus fulvestrant in patients with hormone receptor-positive (HR+), HER2-negative advanced breast cancer (ABC). This study assessed patient-reported pain, global health-related quality of life (HRQoL), functioning, and symptoms. MATERIALS AND METHODS:Abemaciclib or placebo (150 p.o. mg twice daily) plus fulvestrant (500 mg, per label) were randomly assigned (2:1). The modified Brief Pain Inventory, Short Form (mBPI-sf); European Organization for Research and Treatment of Cancer (EORTC) QoL Core 30 (QLQ-C30); and Breast Cancer Questionnaire (QLQ-BR23) assessed outcomes. Data were collected at baseline, cycle 2, every two cycles 3-13, thereafter at every three cycles, and 30?days postdiscontinuation. Longitudinal mixed regression and Cox proportional hazards models assessed postbaseline change and time to sustained deterioration (TTSD) by study arm. RESULTS:On-treatment HRQoL scores were consistently maintained from baseline and similar between arms. Patients in the abemaciclib arm (n =?446) experienced a 4.9-month delay in pain deterioration (mBPI-sf), compared with the control arm (n =?223), and significantly greater TTSD on the mBPI-sf and analgesic use (hazard ratio, 0.76; 95% CI, 0.59-0.98) and QLQ-C30 pain item (hazard ratio, 0.62; 95% CI, 0.48-0.79). TTSD for functioning and most symptoms significantly favored the abemaciclib arm, including fatigue, nausea and vomiting, and cognitive and social functioning. Only diarrhea significantly favored the control arm (hazard ratio, 1.60; 95% CI, 1.20-2.10). CONCLUSION:HRQoL was maintained on abemaciclib plus fulvestrant. Alongside superior PFS and manageable safety profile, results support treatment with abemaciclib plus fulvestrant in a population of patients with endocrine-resistant HR+, HER2-negative ABC. IMPLICATIONS FOR PRACTICE:In MONARCH 2, abemaciclib plus fulvestrant demonstrated superior efficacy and a manageable safety profile for patients with in hormone receptor-positive (HR+), HER2-negative (-) advanced breast cancer (ABC). Impact on health-related quality of life (HRQoL) is important to consider, given the palliative nature of ABC treatment. In this study, abemaciclib plus fulvestrant, compared with placebo plus fulvestrant, significantly delayed sustained deterioration of pain and other patient-reported symptoms (including fatigue, nausea, vomiting), and social and cognitive functioning. Combined with demonstrated clinical benefit and tolerability, the stabilization of patient-reported symptoms and HRQoL further supports abemaciclib plus fulvestrant as a desirable treatment option in endocrine resistant, HR+, HER2- ABC.

Dataset Information

Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.

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Preclinical characterization of abemaciclib in hormone receptor positive breast cancer.

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