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

Sunisa Prasopporn; Orawan Suppramote; Ben Ponvilawan; Chanette Jamyuang; Jantappapa Chanthercrob; Amphun Chaiboonchoe; Pimkanya More-Krong; Kamonchanok Kongsri; Monthira Suntiparpluacha; Rawisak Chanwat; Krittiya Korphaisarn; Seiji Okada; Somponnat Sampattavanich; Siwanon Jirawatnotai

doi:10.3389/fonc.2022.1021632

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

Front Oncol. 2022 Nov 30:12:1021632. doi: 10.3389/fonc.2022.1021632. eCollection 2022.

Authors

Sunisa Prasopporn^{1

2}, Orawan Suppramote^{2

3}, Ben Ponvilawan², Chanette Jamyuang², Jantappapa Chanthercrob¹, Amphun Chaiboonchoe¹, Pimkanya More-Krong¹, Kamonchanok Kongsri¹, Monthira Suntiparpluacha¹, Rawisak Chanwat⁴, Krittiya Korphaisarn⁵, Seiji Okada⁶, Somponnat Sampattavanich^{1

2}, Siwanon Jirawatnotai^{1

2}

Affiliations

¹ Siriraj Center of Research Excellence for Precision Medicine and Systems Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
² Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
³ Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, Thailand.
⁴ Hepato-Pancreato-Biliary Surgery Unit, Department of Surgical Oncology, National Cancer Institute, Bangkok, Thailand.
⁵ Division of Medical Oncology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁶ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.

Abstract

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 in vivo 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 in vitro and in vivo 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.

Keywords: Gemcitabine plus Cisplatin therapy; LCL161; SMAC mimetics; acquired vulnerability; cholangiocarcinoma; multidrug resistance.

Grants and funding

This study was funded by grants from the National Science and Technology Development Agency (NSTDA) of Thailand, the Japan Science and Technology Agency, and the National Institute of Allergy and Infectious Diseases of the United States as part of the e-ASIA Joint Research Program (e-ASIA JRP); the NSTDA (P-15-50208), the National Research Council of Thailand (NRCT) R016441034, the Advanced Research in Pharmacology Fund, Siriraj Foundation (D003421), and by Mahidol University (Basic Research Fund, and the grant of fiscal year 2022).