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

• Published in: Frontiers in oncology Vol. 12; p. 1021632
• Main Authors: Prasopporn, Sunisa, Suppramote, Orawan, Ponvilawan, Ben, Jamyuang, Chanette, Chanthercrob, Jantappapa, Chaiboonchoe, Amphun, More-Krong, Pimkanya, Kongsri, Kamonchanok, Suntiparpluacha, Monthira, Chanwat, Rawisak, Korphaisarn, Krittiya, Okada, Seiji, Sampattavanich, Somponnat, Jirawatnotai, Siwanon
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 30-11-2022
• Subjects: acquired vulnerability; cholangiocarcinoma; Gemcitabine plus Cisplatin therapy; LCL161; multidrug resistance; Oncology; SMAC mimetics; SMAC mimetics; multidrug resistance; Gemcitabine plus Cisplatin therapy; LCL161; cholangiocarcinoma; acquired vulnerability
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2022.1021632

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
GEM/CIS-resistant xenograft models. A strong synergic effect was observed when LCL161 was added to GEM/CIS. Interestingly, this synergism was also observed in drug-naïve CCA cell lines, xenografts, and patient-derived organoids. This triplet therapy also prevented the emergence of multidrug-resistant CCA in
and
models. Our findings suggest that activation of cIAP2 allows CCA to escape GEM/CIS, and that suppression of cIAP2 reestablishes the apoptotic profile of CCA, thus restoring its vulnerability to GEM/CIS. The results of this study indicate that combining the SMAC mimetic LCL161 with GEM/CIS inhibits and prevents the emergence of multidrug resistance in CCA.