Chronic arsenic trioxide exposure leads to enhanced aggressiveness via Met oncogene addiction in cancer cells

Abstract

As an environmental poison, arsenic is responsible for many cancer deaths. Paradoxically, arsenic trioxide (ATO) presents also a powerful therapy used to treat refractory acute promyelocytic leukemia (APL) and is intensively investigated for treatment of other cancer types. Noteworthy, cancer therapy is frequently hampered by drug resistance, which is also often associated with enhancement of tumor aggressiveness.In this study, we analyzed ATO-selected cancer cells (A2780ATO) for the mechanisms underlying their enhanced tumorigenicity and aggressiveness. These cells were characterized by enhanced proliferation and spheroid growth as well as increased tumorigenicity of xenografts in SCID mice. Noteworthy, subsequent studies revealed that overexpression of Met receptor was the underlying oncogenic driver of these effects, as A2780ATO cells were characterized by collateral sensitivity against Met inhibitors. This finding was also confirmed by array comparative genomic hybridization (array CGH) and whole genome gene expression arrays, which revealed that Met overexpression by chronic ATO exposure was based on the transcriptional regulation via activation of AP-1. Finally, it was shown that treatment with the Met inhibitor crizotinib was also effective against A2780ATO cell xenografts in vivo, indicating that targeting of Met presents a promising strategy for the treatment of Met-overexpressing tumors after either arsenic exposure or failure to ATO treatment.

Outcome of EGFR-mutated NSCLC patients with MET-driven resistance to EGFR tyrosine kinase inhibitors

“…In our study, all the patients with a MET amplification who also underwent a MET IHC were scored 3+. MET overexpression, regardless MET amplification status, has been found to induce addiction to the MET pathway, and was recently found in 27.1% of EGFR mutated NSCLC with acquired resistance to EGFR TKI [ 29 ] [ 17 ]. Moreover, an ongoing clinical trial evaluating the efficacy of combining MET and EGFR TKIs in EGFR -mutated NSCLC patients with MET-driven resistance to EGFR TKIs includes patients with both MET amplification or MET overexpression (NCT01610336).…”

Promoter methylation patterns of ABCB1, ABCC1 and ABCG2 in human cancer cell lines, multidrug-resistant cell models and tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients

“…Isolation of total RNA and whole genome gene expression arrays were performed as described in [ 55 , 56 ]. Single or dual color experiments were performed according to the instructions provided by Agilent using the Quick Amp Labeling Kit .…”

Distinct activity of the bone-targeted gallium compound KP46 against osteosarcoma cells - synergism with autophagy inhibition

“…Stained cells were observed under the microscope and microphotographs taken (Nikon Eclipse Ti, Life-Cell Imaging) before dilution in FACS-PBS. Flow cytometry was performed using LSRFortessa flow cytometer and data analyzed with Flowing Software (University of Turku, Finland) [ 25 ]. Fluorescence intensity was measured with the following filter settings: FL3 – red (488 nm/670 nm) and FL1 –green (488 nm/533 nm).…”