Liver X receptor agonist T0901317 reverses resistance of A549 human lung cancer cells to EGFR‐TKI treatment

Abstract

Epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) is effective in lung cancer patients carrying sensitive EGFR mutations. In this study, we investigated if liver X receptor (LXR) agonist T0901317 could reverse the resistance of lung cancer cell lines A549 and H1650 to EGFR‐TKI treatment. We found that T0901317 could make natural EGFR‐TKI‐resistant A549 human lung cancer cells sensitive to EGFR‐TKI treatment and that this was dependent on LXRβ expression. However, T0901317 does not have a similar effect on another natural EGFR‐TKI‐resistant cell line H1650.

Synergistic tumor suppression by a Perilla frutescens-derived methoxyflavanone and anti-cancer tyrosine kinase inhibitors in A549 human lung adenocarcinoma

“…PDMF and anti-cancer TKIs synergistically suppress cell proliferation of A549 human lung cancer cells A549 human lung adenocarcinoma cells are used as a model of EGFR-TKI-resistant NSCLC cells (Ito et al 2014;Cao et al 2016). For those EGFR-TKI-resistant cells, the Bcr-Abl type of TKIs may offer alternative anti-cancer agent, since the EGFR-TKI-resistant A549 cells indeed show a good response to a Bcr-Abl TKI (Zhang et al 2003), probably because of its crossreaction to a wide array of oncogenic TKs.…”

Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics

“…The literature is sparse on direct connections between cholesterol efflux factors and targeted or immunotherapy of lung cancer. However, agonism of the cholesterol efflux regulator LxR has been shown to sensitize lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment [114,115]. More intriguingly, therapeutic LxR agonism reduced myeloid-derived suppressor cells (MDSC) abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial [116].…”

Liver X receptor agonist T0901317 inhibits the migration and invasion of non-small-cell lung cancer cells in vivo and in vitro

“…However, with persistent use of TKI molecular targeted therapy alone, NSCLC patients eventually develop TKI resistance, leading to treatment failure [2,[7][8][9]. Liver X receptors (LXRs) belong to the nuclear receptor superfamily and are ligand-activated transcriptional factors [10][11][12][13]. LXRs are recognized as important regulators of cholesterol, fatty acid metabolism, inflammatory responses, and glucose homeostasis [14][15][16].…”

“…Two isoforms have been described: LXRα and LXRβ. LXRα is highly expressed in the liver and at lower levels in the lungs, adrenal glands, intestine, adipose, macrophages, and kidneys, whereas LXRβ is ubiquitously expressed [11,17]. Natural and synthetic ligands have already been developed and have effective therapeutic properties in murine models, where they have been used for the treatment of diabetes, atherosclerosis, and Alzheimer's disease [18,19].…”