SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells

Abstract

Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c-IAP1, c-IAP2, and XIAP. Non-canonical NF-κB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143-containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here.

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer

“…BRD induced oncogenic signaling appears to be pervasive in all breast cancer subtypes (25); disrupting BRD function in basal-like breast cancer suppressed tumorigenesis (26), and TNBCs appear to be preferentially sensitive to BRD inhibition (27). We have recently reported anticancer activity of JQ1 in drug combinations in vitro and in vivo (28). Interestingly, JQ1 was also found to synergize with RTK inhibitors, erlotinib, XL-184, and crizotinib.…”

Combinatorial Screening of Pancreatic Adenocarcinoma Reveals Sensitivity to Drug Combinations Including Bromodomain Inhibitor Plus Neddylation Inhibitor

“…Several of our top combinations affected immune/inflammatory signaling pathways. Immune signaling is an important component of PDAC development (34-36) and apoptosis modulators work in conjunction with immune response signaling pathways, such as JAK/STAT3/NF-κB axis control of BCL-2 expression (37). STAT3 promotes PDAC with mutant KRAS in PDAC mouse models (38).…”

Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells

“…These findings suggest that targeting of IAPs or BCL-2 family members could be beneficial for paclitaxel-treated TNBC patients. Indeed, it was shown that SMAC mimetics potentiate paclitaxel-mediated ovarian cancer cell death in vitro and in vivo [35] and similar effects were reported for NSCLC [14, 15] and breast cancer [16]. Likewise, administration of navitoclax (ABT-263) enhanced taxane-based treatment of ovarian cancer [36] and NSCLC [37].…”