Frontiers in Oncology (Nov 2022)

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

  • Sunisa Prasopporn,
  • Sunisa Prasopporn,
  • Orawan Suppramote,
  • 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,
  • Somponnat Sampattavanich,
  • Siwanon Jirawatnotai,
  • Siwanon Jirawatnotai

DOI
https://doi.org/10.3389/fonc.2022.1021632
Journal volume & issue
Vol. 12

Abstract

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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.

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