Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required. To that end - in this study, we developed several acquired GEM/CIS-resistant CCA cell lines and we screened those cell lines for acquired vulnerability. The screening process revealed that subset of CCA with GEM/CIS resistance acquired vulnerability to the small-molecule second mitochondrial-derived activator of caspases (SMAC) mimetics LCL161 and Birinapant. The observed acquired vulnerability was found to be associated with upregulation of an inhibitor of apoptosis protein 2 (cIAP2), a known target of SMAC mimetics. LCL161 or cIAP2-shRNA downregulated cIAP2 and restored the sensitivity to GEM/CIS in GEM/CIS-resistant CCA cell lines and in

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Copyright © 2022 Prasopporn, Suppramote, Ponvilawan, Jamyuang, Chanthercrob, Chaiboonchoe, More-Krong, Kongsri, Suntiparpluacha, Chanwat, Korphaisarn, Okada, Sampattavanich and Jirawatnotai.

Déclaration de conflit d'intérêts

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.