PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells

Patel, Atish; Tiwari, Amit K.; Chufán, Eduardo E.; Sodani, Kamlesh; Anreddy, Nagaraju; Singh, Satyakam; Ambudkar, Suresh V.; Stephani, Ralph A.; Chen, Zhe‐Sheng

doi:10.1007/s00280-013-2184-z

Cited by 43 publications

(37 citation statements)

References 43 publications

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“…However, knowledge of the impact of ABC transporters on resistance against FGFR TKIs is limited. So far, only reversal of ABCB1-mediated MDR by the pan-FGFR/VEGFR inhibitor PD173074 and, in agreement with our here presented data, also nintedanib has been described [33, 34]. In the current study we demonstrate that high level expression of ABCB1 is underlying acquired nintedanib resistance of the FGFR1-driven SCLC cell line DMS114 but not of the two NSCLC cell lines NCI-H1703 and NCI-H520.…”

Section: Discussionsupporting

confidence: 90%

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

et al. 2016

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Genomically amplified fibroblast growth factor receptor 1 (FGFR1) is an oncogenic driver in defined lung cancer subgroups and predicts sensibility against FGFR1 inhibitors in this patient cohort. The FGFR inhibitor nintedanib has recently been approved for treatment of lung adenocarcinoma and is currently evaluated for small cell lung cancer (SCLC). However, tumor recurrence due to development of nintedanib resistance might occur. Hence, we aimed at characterizing the molecular mechanisms underlying acquired nintedanib resistance in FGFR1-driven lung cancer. Chronic nintedanib exposure of the FGFR1-driven SCLC cell line DMS114 (DMS114/NIN) but not of two NSCLC cell lines induced massive overexpression of the multidrug-resistance transporter ABCB1. Indeed, we proved nintedanib to be both substrate and modulator of ABCB1-mediated efflux. Importantly, the oncogenic FGFR1 signaling axis remained active in DMS114/NIN cells while bioinformatic analyses suggested hyperactivation of the endothelin-A receptor (ETAR) signaling axis. Indeed, ETAR inhibition resensitized DMS114/NIN cells against nintedanib by downregulation of ABCB1 expression. PKC and downstream NFκB were identified as major downstream players in ETAR-mediated ABCB1 hyperactivation. Summarizing, ABCB1 needs to be considered as a factor underlying nintedanib resistance. Combination approaches with ETAR antagonists or switching to non-ABCB1 substrate FGFR inhibitors represent innovative strategies to manage nintedanib resistance in lung cancer.

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Section: Discussionsupporting

confidence: 90%

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

et al. 2016

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“…16 In vivo and in vitro studies suggested that PD173074 inhibited FGF-induced neoangiogenesis and tumor growth while being exempt of general toxicity. [14][15][16][17] In this study, we found intraperitoneal injection of 20 mg/kg PD173074 decreased pulmonary arterial pressure and alleviated pulmonary vascular remolding. This was consistent with the previous studies that FGFR inhibition with SU5402 or dovitinib reversed pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 90%

“…13 PD173074 could block the proliferation and clonogenic growth as well as induce cancer cell-cycle arrest and apoptosis in a variety of cancer cell lines. [14][15][16] When used in vivo, this compound was shown to inhibit FGF-driven angiogenesis and tumor growth with no apparent general toxicity. 17 Therefore, it is regarded as a promising compound for in vivo inhibition of FGF signaling.…”

Section: Introductionmentioning

confidence: 98%

Inhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II Expression

Zheng

et al. 2015

Journal of Cardiovascular Pharmacology

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“…A number of chemosensitizers inhibiting eukaryotic ABC transporters and overcoming drug resistance in cancer cells were in clinical development (24,25). Although sensitizers that inhibit bacterial RND pump-mediated efflux so far have not been available for clinical use, such compounds have been described and include 1-(1-naphthylmethyl)-piperazine (NMP) and phenylalanine-arginine-␤-naphthylamide (PA␤N).…”

mentioning

confidence: 99%

Random Mutagenesis of the Multidrug Transporter AcrB from Escherichia coli for Identification of Putative Target Residues of Efflux Pump Inhibitors

Schuster¹,

Kohler

Buck³

et al. 2014

Antimicrob Agents Chemother

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Efflux is an important mechanism of bacterial multidrug resistance (MDR), and the inhibition of MDR pumps by efflux pump inhibitors (EPIs) could be a promising strategy to overcome MDR. 1-(1-Naphthylmethyl)-piperazine (NMP) and phenylalaninearginine-␤-naphthylamide (PA␤N) are model EPIs with activity in various Gram-negative bacteria expressing AcrB, the major efflux pump of Escherichia coli, or similar homologous pumps of the resistance-nodulation-cell division class. The aim of the present study was to generate E. coli AcrB mutants resistant to the inhibitory action of the two model EPIs and to identify putative EPI target residues in order to better understand mechanisms of pump inhibition. Using an in vitro random mutagenesis approach focusing on the periplasmic domain of AcrB, we identified the double mutation G141D N282Y, which substantially compromised the synergistic activity of NMP with linezolid, was associated with similar intracellular linezolid concentrations in the presence and absence of NMP, and did not impair the intrinsic MICs of various pump substrates and dye accumulation. We propose that these mutations near the outer face of the distal substrate binding pocket reduce NMP trapping. Other residues found to be relevant for efflux inhibition by NMP were G288 and A279, but mutations at these sites also changed the susceptibility to several pump substrates. Unlike with NMP, we were unable to generate AcrB periplasmic domain mutants with resistance or partial resistance to the EPI activity of PA␤N, which is consistent with the modes of action of PA␤N differing from those of NMP.

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PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells

Abstract: Here, we report for the first time, PD173074, an inhibitor of the FGFR, to selectively reverse ABCB1 transporter-mediated MDR by directly blocking the efflux function of the transporter.

Cited by 43 publications

References 43 publications

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

Inhibition of FGFR Signaling With PD173074 Ameliorates Monocrotaline-induced Pulmonary Arterial Hypertension and Rescues BMPR-II Expression

Random Mutagenesis of the Multidrug Transporter AcrB from Escherichia coli for Identification of Putative Target Residues of Efflux Pump Inhibitors

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