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

Abstract

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.

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…In a small cell lung cancer group of patients with FGFR1 amplification treated with Nintedanib might occur a resistance. This specific resistance is induced by an overexpression of the multidrug-resistance transporter ABCB, so, a strategy could be, use FGFR1 inhibitors with a drug that downregulates ABCB1 such as ETAR antagonist (Englinger et al, 2016). Recently, a study analyzed the most common FGFR alterations that cause resistance to therapy in preclinical models.…”

Potential Therapeutic Strategies for Lung and Breast Cancers through Understanding the Anti-Angiogenesis Resistance Mechanisms

“…Metabolic symbiosis, which is the generation of ATP by using lactate from tumor cells suffering from hypoxia, is another resistance-mediating mechanism [86]. Nintedanib, a drug that acts via the inhibition of angiogenesis-related kinases, has potent activity in the treatment of NSCLC and breast cancer [87,88]. Moreover, nintedanib has been assessed for resistance induction.…”

Mapping the Human Kinome in Response to DNA Damage

“…Survival circos plot with DNA repair deficient cells ( Figure S1) was created using TOPS (Muellner et al, 2014) for analysis and basic visualization. For kinome survival to DNA damage ( Figure 1, Table S1), areas under the curve (AUC) were calculated as a cumulative measure of compound potency by taking the sum of the mean of subsequent concentration points (as applied previously (Englinger et al, 2016)).…”