Acquisition of cancer stem cell‐like properties in non‐small cell lung cancer with acquired resistance to afatinib

Hashida, Shinsuke; Yamamoto, Hiromasa; Shien, Kazuhiko; Miyoshi, Yukiko; Ohtsuka, Tomoaki; Suzawa, Ken; Watanabe, Masahide; Maki, Yuho; Soh, Junichi; Asano, Hiroaki; Tsukuda, Kazunori; Miyoshi, Shinichiro; Toyooka, Shinichi

doi:10.1111/cas.12749

Cited by 69 publications

(83 citation statements)

References 39 publications

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“…Recently, also acquisition of EGFR and MET inhibitor resistance was occasionally connected with ABCB1 overexpression and concerned afatinib and erlotinib as well as PHA-665752, respectively [39, 40]. In the case of afatinib and PHA-665752 resistance, upregulation of ABCB1 expression was connected with selection for a cancer stem cell phenotype and an epithelial-to-mesenchymal transition (EMT) switch [41]. In our study, however, selection of a DMS114 cell subclone with enhanced stemness during nintedanib selection seems unlikely.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…A number of diverse mechanisms have been shown to underlie the development of acquired resistance to EGFR‐TKIs in NSCLC, which makes it difficult to overcome the drug resistance to EGFR‐TKIs. Starting with the report of the appearance of a secondary EGFR T790M mutation in 2005, numerous resistance mechanisms have been reported by our group and others, such as MET amplification, activation of the mesenchymal‐epithelial transition factor/hepatocyte growth factor axis, induction of epithelial‐to‐mesenchymal transition (EMT), acquisition of stem cell properties, and transformation from NSCLC into small cell lung cancer . Recently, osimertinib, a third‐generation EGFR‐TKI, was developed to overcome the resistance associated with the EGFR T790M mutation, and is expected to play an important role in the treatment of advanced NSCLC .…”

Section: Introductionmentioning

confidence: 99%

“…To the best of our knowledge, the efficacy of the combined therapy with MEK and PI3K inhibitors for NSCLC after TKI failure has not been fully elucidated. In this study, we examined the effect of MEK plus PI3K dual inhibition on the cell growth of NSCLC with acquired resistance to EGFR‐TKIs using experimentally established EGFR‐TKI‐resistant cell lines, and explored the therapeutic potential of MEK/PI3K dual blockade therapy.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

et al. 2018

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Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.

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“…Another study by Kobayashi et al (29) reported that Oct-4, the putative stem cell marker, could induce gefitinib resistance by regulating the CSC properties in aNSCLC cell line with EGFR mutation, and the samples from patients with acquired resistance to TKIs manifested a high level of Oct-4 expression. Similarly, cells resistant to the second generation TKI afatinib manifested CSC phenotypes, including an enhanced ability of colony formation and proliferation, and increased level of ALDH1 and CD44 (30). So it was implied that resistance to TKI could partly arise from CSCs.…”

Section: Discussionmentioning

confidence: 99%

EGFR-TKI resistance and MAP17 are associated with cancer stem cell like properties

Shao

Zhong

et al. 2018

Oncol Lett

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Abstract.Patients with non-small-cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations generally react well to tyrosine kinase inhibitors (TKIs). However acquired resistance eventually occurs. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification and PIK3CA mutation. In recent years, cancer stem cells (CSCs) have been suggested to be involved in TKI resistance. MAP17 is aberrantly overexpressed in a number of malignancies. However, the expression pattern and function of MAP17 in CSCs are still unclear. The aim the present study was to illustrate the effect of CSC-like cells on the resistance to TKIs in EGFR mutant NSCLC cells and explore the possible role of MAP17 in CSCs. The EGFR mutant cell line PC9 was cultured under serum-deprived undifferentiated conditions. The CSC properties including expression of stem cell markers CD133, CD44, Oct-4 and ABCG2, ability of self-renewal, invasion, proliferation and tumorigenesis were examined. The expression of MAP17 was compared in sphere and parent cells. Sphere cells displayed stem cells phenotypes and were resistant to erlotinib. Sphere cells expressed higher levels of MAP17, and MAP17 was associated with self-renewal and TKI resistance. The function of MAP17 demonstrated to be partially dependent on Na-dependent glucose transporter 1. Collectively these findings suggest that MAP17 serves a role in TKI resistance through regulation of CSCs in lung cancer.

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Acquisition of cancer stem cell‐like properties in non‐small cell lung cancer with acquired resistance to afatinib

Cited by 69 publications

References 39 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

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

EGFR-TKI resistance and MAP17 are associated with cancer stem cell like properties

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