Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance

• Published in: British journal of cancer Vol. 116; no. 4; pp. 489 - 500
• Main Authors: Englinger, B, Mair, M, Miklos, W, Pirker, C, Mohr, T, van Schoonhoven, S, Lötsch, D, Körner, W, Ferk, F, Knasmüller, S, Heffeter, P, Keppler, B K, Grusch, M, Berger, W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-02-2017; Nature Publishing Group
• Subjects: 631/45/474/2073; 692/4028/67/1059/2326; 692/699/67/1059; 692/699/67/1504/1885; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cisplatin - therapeutic use; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Cullin Proteins - antagonists & inhibitors; Cullin Proteins - genetics; Dioxoles - therapeutic use; DNA damage; DNA Repair - drug effects; DNA Repair - genetics; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epidemiology; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Genes, p53; Growth factors; HCT116 Cells; Humans; Kinases; Medical research; Molecular Medicine; Oncology; Proteins; RNA, Small Interfering - pharmacology; Tetrahydroisoquinolines - therapeutic use; Translational Therapeutics; Austria; CUL4A; NER; colorectal cancer; cisplatin; trabectedin
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2016.449

Background:
Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens.
Methods:
Human HCT116 CRC cells were selected for acquired trabectedin resistance
in vitro
and characterised by cell biological as well as bioinformatic approaches.
In vivo
xenograft experiments were conducted.
Results:
Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment.
Conclusions:
Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.