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

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.

Pro-apoptotic Smac/DIABLO Acts as an Independent Prognostic Factor in Oral Squamous Cell Carcinoma

“…Through pharmacological combination, Yu et al [47] elucidated the utilization of Doxorubicin in combination with SBP-0636457, a Smac-mimetic compound, in cotreatment, which resulted in the induction of necroptosis rather than apoptosis in breast cancer cells. Conversely, Prasopporn et al [50] demonstrated that Smac-mimetic LCL161 combined with Gemcitabine and Cisplatin therapy effectively inhibits the development of multidrug resistance in a rare subtype of gastric cancer. Dmello et al [51], also demonstrated treatment of LCL161 and Bazedoxifene in chemotherapy enhanced tumor cell apoptosis in CCR.…”

Cisplatin in Liver Cancer Therapy

“…The recent study on GEM sensitivity to CCA showed that serum thrombospondin-1 (TSP1) could predict gemcitabine sensitivity in CCA patients, and in a functional analysis, TSP1 enhanced the effect of GEM [ 205 ]. Interestingly, a basic study that established GEM/CIS-resistant CCA cells and analyzed their resistance mechanism showed that resistant CCA acquired vulnerability to the molecular second mitochondrial activator of caspase (SMAC) mimetics, LCL161 and Birinapant, and was associated with increased expression of apoptosis inhibitory protein 2 (cIAP2), a known target of SMAC mimetics [ 206 ]. Analysis in xenograft models of GEM/CIS-resistant CCA cells also showed that LCL161 downregulated clAP2 expression and restored sensitivity to GEM/CIS, suggesting that the combination of LCL161 and GEM/CIS could prevent the emergence of drug resistance in CCA.…”