Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP

Vries, Nienke A. de; Buckle, Tessa; Zhao, Jin; Beijnen, Jos H.; Schellens, Jan H.M.; Tellingen, Olaf van

doi:10.1007/s10637-010-9569-1

Cited by 133 publications

(106 citation statements)

References 39 publications

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“…According to the above results, lots of researchers put forward the subtle relationship between BBB permeability and tumor‐resistance protein that could remove toxins, drugs, or chemotherapies from the CNS. It would be a primary reason of failure to some extent 63. Besides, the EGFR T790M mutation could be another important mechanism for resistance to EGFR TKIs 64.…”

Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood‐brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted “seed and soil” hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis—lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain‐specific therapies will be developed for brain metastasis.

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Section: The Mechanism Of Brain Metastasismentioning

confidence: 99%

Emerging findings into molecular mechanism of brain metastasis

Chen

2018

Cancer Medicine

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“…In particular, the drug efflux transporters expressed at the BBB play a very important role in limiting the brain penetration of a wide variety of compounds including frequently used chemotherapeutics and novel targeted agents. Two well-established drug efflux transporters, ABCB1 (P-glycoprotein, P-gp, MDR1) and ABCG2 (Breast Cancer Resistance Protein, BCRP), are abundantly expressed in the human and murine BBB and restrict most newly developed kinase inhibitors such as erlotinib, lapatinib, and palbociclib (15)(16)(17). As a consequence, the usefulness of such agents in glioblastoma treatment might be attenuated by an inadequate brain penetration.…”

Section: Introductionmentioning

confidence: 99%

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

Lin

Gooijer

Hanekamp

et al. 2017

Clinical Cancer Research

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Purpose: The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma and offers several druggable targets. However, clinical efficacy of PI3K/mTOR inhibitors in glioblastoma has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against glioblastoma. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs.Experimental Design: We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wild-type and ABC-transporter knockout mice. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.Results: The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1, whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055, but not ZSTK474 or rapamycin. Concordantly, Abcb1a/bÀ/À mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold), and NVP-BEZ235 (4.5-fold), but not ZSTK474 relative to WT mice. Importantly, ABC transporters limited rapamycin brain penetration to subtherapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition.

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“…This is probably due to the inhibition of P-gp, also induced by verapamil. De Vries et al [45] also suggested the involvement of P-gp in the efflux of erlotinib. Giannoudis et al [42] and Gromicho et al [43] suggested that P-gp is also involved in dasatinib dependent efflux.…”

Section: Discussionmentioning

confidence: 98%