A phase II study of afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole

Gunzer, K.; Joly, Florence; Ferrero, Jean-­Marc; Gligorov, Joseph; Mont-Serrat, H. de; Uttenreuther-Fischer, Martina; Pelling, Katy; Wind, Sven; Bousquet, Guilhem; Misset, Jean-Louis

doi:10.1186/s40064-015-1601-7

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…The drug AICAR, which targets AMPK, have shown to have anti-proliferative effects in ER-positive breast cancer cell lines [ 22 ]. Further, a Phase II clinical trial demonstrated that BIBW2992 was able to induce stable disease in more than 50% of ER-positive metastatic breast cancer that has progressed on letrozole monotherapy when used in combination with letrozole [ 23 ]. DeSigN also predicted resistance of ER-positive breast cancer cells against drugs with strong negative Connectivity Score such as dasatinib and midostaurin.…”

Section: Resultsmentioning

confidence: 99%

DeSigN: connecting gene expression with therapeutics for drug repurposing and development

et al. 2017

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BackgroundThe drug discovery and development pipeline is a long and arduous process that inevitably hampers rapid drug development. Therefore, strategies to improve the efficiency of drug development are urgently needed to enable effective drugs to enter the clinic. Precision medicine has demonstrated that genetic features of cancer cells can be used for predicting drug response, and emerging evidence suggest that gene-drug connections could be predicted more accurately by exploring the cumulative effects of many genes simultaneously.ResultsWe developed DeSigN, a web-based tool for predicting drug efficacy against cancer cell lines using gene expression patterns. The algorithm correlates phenotype-specific gene signatures derived from differentially expressed genes with pre-defined gene expression profiles associated with drug response data (IC50) from 140 drugs. DeSigN successfully predicted the right drug sensitivity outcome in four published GEO studies. Additionally, it predicted bosutinib, a Src/Abl kinase inhibitor, as a sensitive inhibitor for oral squamous cell carcinoma (OSCC) cell lines. In vitro validation of bosutinib in OSCC cell lines demonstrated that indeed, these cell lines were sensitive to bosutinib with IC50 of 0.8–1.2 μM. As further confirmation, we demonstrated experimentally that bosutinib has anti-proliferative activity in OSCC cell lines, demonstrating that DeSigN was able to robustly predict drug that could be beneficial for tumour control.ConclusionsDeSigN is a robust method that is useful for the identification of candidate drugs using an input gene signature obtained from gene expression analysis. This user-friendly platform could be used to identify drugs with unanticipated efficacy against cancer cell lines of interest, and therefore could be used for the repurposing of drugs, thus improving the efficiency of drug development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3260-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

DeSigN: connecting gene expression with therapeutics for drug repurposing and development

et al. 2017

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“…The pharmacokinetics of afatinib have been studied in combination with standard chemotherapy agents, including letrozole [ 47 ], paclitaxel [ 48 ], pemetrexed [ 49 ], docetaxel [ 50 ], vinorelbine [ 51 ], temozolomide [ 52 ], trastuzumab [ 53 , 54 ], nintedanib [ 55 ], carboplatin [ 56 ], paclitaxel/bevacizumab [ 56 ], cisplatin/paclitaxel [ 56 , 57 ] and cisplatin/5-fluorouracil [ 57 ]. In most of these studies, the primary objective was to determine the maximum tolerated dose of the combination treatment in patients with advanced solid tumours.…”

Section: Drug–drug Interactionsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

et al. 2016

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Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20–50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0440-1) contains supplementary material, which is available to authorized users.

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“…The protein kinases AKT (also called PKB) and PKC are substrates of dimerized ErbB receptor RTKs [7]. Consequently, the ErbB receptor-mediated cytosolic phosphorylation activity is a reporter for the induction of malignant transformation in breast epithelium, and blocking ErbB activity acts supportive in breast cancer chemotherapy [8]. This can be recorded by correlative microscopy covering the

μ

m as well as the nm cytosol regime.…”

Section: Introductionmentioning

confidence: 99%

Localisation Microscopy of Breast Epithelial ErbB-2 Receptors and Gap Junctions: Trafficking after γ-Irradiation, Neuregulin-1β, and Trastuzumab Application

Pilarczyk

Nesnidal

Gunkel

et al. 2017

IJMS

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In cancer, vulnerable breast epithelium malignance tendency correlates with number and activation of ErbB receptor tyrosine kinases. In the presented work, we observe ErbB receptors activated by irradiation-induced DNA injury or neuregulin-1sans-serifβ application, or alternatively, attenuated by a therapeutic antibody using high resolution fluorescence localization microscopy. The gap junction turnover coinciding with ErbB receptor activation and co-transport is simultaneously recorded. DNA injury caused by 4 Gray of 6 MeV photon γ-irradiation or alternatively neuregulin-1sans-serifβ application mobilized ErbB receptors in a nucleograde fashion—a process attenuated by trastuzumab antibody application. This was accompanied by increased receptor density, indicating packing into transport units. Factors mobilizing ErbB receptors also mobilized plasma membrane resident gap junction channels. The time course of ErbB receptor activation and gap junction mobilization recapitulates the time course of non-homologous end-joining DNA repair. We explain our findings under terms of DNA injury-induced membrane receptor tyrosine kinase activation and retrograde trafficking. In addition, we interpret the phenomenon of retrograde co-trafficking of gap junction connexons stimulated by ErbB receptor activation.

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A phase II study of afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole

Cited by 12 publications

References 38 publications

DeSigN: connecting gene expression with therapeutics for drug repurposing and development

DeSigN: connecting gene expression with therapeutics for drug repurposing and development

Clinical Pharmacokinetics and Pharmacodynamics of Afatinib

Localisation Microscopy of Breast Epithelial ErbB-2 Receptors and Gap Junctions: Trafficking after γ-Irradiation, Neuregulin-1β, and Trastuzumab Application

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