Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas

Liang, Muh Lii; Chen, Chun‐Han; Liu, Yun Ru; Huang, Man Hsu; Lin, Yu Chen; Wong, Tai-Tong; Lin, Sey‐En; Chu, Shing Shiung; Ding, Yi; Hsieh, Tsung Han

doi:10.3390/cancers12123597

Cited by 10 publications

(15 citation statements)

References 48 publications

(76 reference statements)

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“…It has been observed that abemaciclib induced cell death by inducing cytoplasmic vacuoles in cancer cells, and massive vacuolization led to atypical cell death, called methuosis ( Huang et al, 2018 ; Hino et al, 2020 ; Liang et al, 2020 ). Here, we found that abemaciclib treatment caused a striking accumulation of cytoplasmic vacuoles in A549 and H1650 cells, when compared with untreated cells ( Figure 2C ).…”

Section: Resultsmentioning

confidence: 99%

Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in Lung Cancer Cells

et al. 2022

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Abemaciclib is a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor approved for the treatment of metastatic breast cancer. Preclinical studies suggest that abemaciclib has the potential for lung cancer treatment. However, several clinical trials demonstrate that monotherapy with abemaciclib has no obvious superiority than erlotinib to treat lung cancer patients, limiting its therapeutic options for lung cancer treatment. Here, we show that the US Food and Drug Administration (FDA)-approved drug, gilteritinib, enhances the cytotoxicity of abemaciclib through inducing apoptosis and senescence in lung cancer cells. Interestingly, abemaciclib in combination with gilteritinib leads to excessive accumulation of vacuoles in lung cancer cells. Mechanistically, combined abemaciclib and gilteritinib induces complete inactivation of AKT and retinoblastoma (Rb) pathways in lung cancer cells. In addition, RNA-sequencing data demonstrate that combination of abemaciclib and gilteritinib treatment induces G2 phase cell-cycle arrest, inhibits DNA replication, and leads to reduction in homologous recombination associated gene expressions. Of note, abemaciclib-resistant lung cancer cells are more sensitive to gilteritinib treatment. In a mouse xenograft model, combined abemaciclib and gilteritinib is more effective than either drug alone in suppressing tumor growth and appears to be well tolerated. Together, our findings support the combination of abemaciclib with gilteritinib as an effective strategy for the treatment of lung cancer, suggesting further evaluation of their efficacy is needed in a clinical trial.

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Section: Resultsmentioning

confidence: 99%

Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in Lung Cancer Cells

et al. 2022

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“…Preclinical studies have shown that abemaciclib inhibits the growth of ependymoma and glioblastoma in xenograft tumor models [10][11]. Moreover, a phase I clinical trial of abemaciclib showed that its concentration in cerebrospinal uid was similar to that in plasma [12].…”

Section: Discussionmentioning

confidence: 99%

Abemaciclib plus fulvestrant for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with cystic brain metastases: a case report and literature review

chu

2022

Preprint

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Cystic brain metastases in patients with breast cancer are rare. They have a worse prognosis than solid brain metastases, and they are less sensitive to radiotherapy. We report a case of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer with cystic brain metastases. The patient underwent treatment with docetaxel combined with capecitabine for 5 months, followed by anastrozole maintenance therapy for 10 months and palbociclib combined with exemestane for 22 months. Cystic brain metastases emerged and bone metastases increased in number. A missense mutation in PIK3CA (exon 10, c.1633G > A [p.Glu545Lys]) was detected by whole-exome next-generation sequencing of peripheral blood samples. After whole-brain radiotherapy (40 Gy/20 fx) combined with 3 months of treatment with everolimus and fulvestrant, cystic brain metastases demonstrated partial regression (PR), but extracranial bone metastases continued to increase in number. Thus, the patient underwent fourth-line treatment with abemaciclib (100 mg bid) combined with fulvestrant (500 mg). Three months later, cystic brain metastases significantly demonstrated PR and extracranial bone metastases were stable, without obvious adverse effects. This is the first report of abemaciclib combined with fulvestrant in the treatment of cystic brain metastases in a patient with HR+/HER2 − breast cancer.

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“…These data indicate that CDK4/6 inhibitors are potential drugs to treat brain tumors. Recent studies have demonstrated that CDK4/6 inhibitors effectively reduced cell proliferation and tumor growth in several brain tumors, including GBMs [ 8 , 9 , 10 , 11 ], AT/RTs [ 12 ], medulloblastomas [ 13 , 14 ] and ependymomas [ 15 ]. Although treatment with CDK4/6 inhibitors alone can delay tumor growth, some evidence demonstrated that CDK4/6 inhibitors induce nongenetic changes resulting in therapeutic failure, such as activation of the PI3K–AKT–mTOR signaling pathway, activation of cyclin E-CDK2 pathway and occurrence of autophagy [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

Hsieh

Liang

Zheng

et al. 2021

Cancers

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Glioblastoma multiforme (GBM) is the most malignant brain tumor in the world, only 25% of GBM patients were alive one year after diagnosis. Although Temozolamide combined with radiation therapy more effectively prolonged the survival rate than radiation alone, the overall survival rate is still dismal. Therefore, a new therapeutic strategy is urgently needed. CDK4/6 inhibitors are newly FDA-approved agents to treat HR-positive, HER2-negative advanced, and metastatic breast cancers, and preclinical results showed that CDK4/6 inhibitors significantly reduced cell proliferation and tumor growth. However, several studies have suggested that CDK4/6 inhibitor-induced non-genetic changes caused treatment failure, including autophagy activation. Therefore, this study aimed to combine an autophagy inhibitor, MPT0L145, with abemaciclib to improve therapeutic efficiency. The use of abemaciclib effectively inhibited cell proliferation via suppression of RB phosphorylation and induced autophagy activation in GBM cancer cells. MPT0L145 treatment alone not only blocked autophagy activation, but also induced generation of ROS and DNA damage in a concentration-dependent manner. Importantly, MPT0L145 had a comparable penetration ability to TMZ in our blood brain barrier permeability assay. Combined MPT0L145 with abemaciclib significantly reduced cell proliferation, suppressed RB phosphorylation, and increased ROS production. In conclusion, the data suggested that blocking autophagy by MPT0L145 synergistically sensitized GBM cancer cells to abemaciclib and represents a potential therapeutic strategy for treating GBM in the future.

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Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas

Cited by 10 publications

References 48 publications

Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in Lung Cancer Cells

Gilteritinib Enhances Anti-Tumor Efficacy of CDK4/6 Inhibitor, Abemaciclib in Lung Cancer Cells

Abemaciclib plus fulvestrant for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with cystic brain metastases: a case report and literature review

Combining an Autophagy Inhibitor, MPT0L145, with Abemaciclib Is a New Therapeutic Strategy in GBM Treatment

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