Birinapant

Metastatic malignant melanoma is the deadliest skin cancer, and it is characterised by its high resistance to apoptosis. The main melanoma driving mutations are part of ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in melanoma. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis...

The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity...

Triple-negative breast cancer (TNBC) is associated with a worse prognosis and higher mortality than other breast cancers, and intensive effort has been made to develop therapies targeting TNBC. TNBC shows higher expression levels of programmed cell death ligand 1 (PD-L1) than other breast cancer types, which leads to a decrease in the killing effects of CD8+ T cells in the tumor microenvironment. Inhibitors of apoptosis proteins (IAPs) could prevent cell death through suppressing caspase activity. Here, Birinapant, an antagonist of IAPs, was found to promote the tumor infiltration of CD8+ T cells via increasing the secretion of the chemokine CXCL9...

Interactions between the inhibitor of apoptosis protein antagonist LCL161 and the histone deacetylase inhibitor panobinostat (LBH589) were examined in human multiple myeloma (MM) cells. LCL161 and panobinostat interacted synergistically to induce apoptosis in diverse MM cell lines, including those resistant to bortezomib (PS-R). Similar interactions were observed with other histone deacetylase inhibitors (MS-275) or inhibitors of apoptosis protein antagonists (birinapant). These events were associated with downregulation of the noncanonical (but not the canonical) NF-κB pathway and activation of the extrinsic, caspase-8-related apoptotic cascade...

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We studied the effects of birinapant, a mimetic of the second mitochondria-derived activator of caspase (SMAC), on invasion and proliferation of MGC-803 gastric cancer cells and the molecular mechanisms underlying these processes. The expression of cellular inhibitor of apoptosis 1 (cIAP1) and TNF receptor-associated factor 3 (TRAF3) in gastric cancer cell line MGC-803 and normal gastric mucosa GES-1 cells were analyzed by Western blotting and cell immunofluorescence assay. After pretreatment of MGC-803 cells with birinapant, a Transwell invasion assay was used to evaluate the cell invasion ability...

Tumour radioresistance is a major problem for cancer radiation therapy. To identify the underlying mechanisms of this resistance, we used human non-small cell lung cancer (NSCLC) cell lines and focused on the Inhibitor of Apoptosis Protein (IAP) family, which contributes to tumourigenesis and chemoresistance. We investigated the possible correlation between radioresistance in six NSCLC cell lines and IAP protein levels and tested the radiosensitizing effect of birinapant in vitro, a molecule that mimics the second mitochondria-derived activator of caspase...

Birinapant is a novel SMAC peptidomimetic molecule in clinical development. It suppresses the inhibitor of apoptosis proteins (IAPs) and promotes cytochrome-C/Apaf-1/caspase-9 activation to induce effective apoptosis. Because IAP inhibition has been shown to enhance the sensitivity of cancer cells to radiation, we investigated the role of birinapant in radiosensitization of glioblastoma cells in vitro and in vivo. Two glioblastoma cell lines, U-251 and U-87, were used to analyze radiosensitization in vitro with 7-AAD cell death/apoptosis and clonogenic assays...

Head and neck squamous cell carcinomas (HNSCC) induced by human papillomavirus (HPV) have increased recently in the US. However, the distinct alterations of molecules involved in the death pathways and drug effects targeting inhibitor of apoptosis proteins (IAPs) have not been extensively characterized in HPV(+) HNSCC cells. In this study, we observed the distinct genomic and expression alterations of nine genes involved in cell death in 55% HNSCC tissues, which were associated with HPV status, tumor staging, and anatomic locations...

Resistance to chemotherapy-induced cell death is a major barrier to effective treatment of solid tumours such as colorectal cancer, CRC. Herein, we present a study aimed at developing a proteomics-based predictor of response to standard-of-care (SoC) chemotherapy in combination with antagonists of IAPs (inhibitors of apoptosis proteins), which have been implicated as mediators of drug resistance in CRC. We quantified the absolute expression of 19 key apoptotic proteins at baseline in a panel of 12 CRC cell lines representative of the genetic diversity seen in this disease to identify which proteins promote resistance or sensitivity to a model IAP antagonist [birinapant (Bir)] alone and in combination with SoC chemotherapy (5FU plus oxaliplatin)...

Elevated activity of bone-degrading osteoclasts (OC) contributes to pathological bone degradation in diseases such as multiple myeloma. Several proinflammatory cytokines, including TNF, contribute to osteoclastogenesis. The receptor-interacting protein kinase 1 (RIPK1) regulates inflammation and cell death. It is recruited to the TNF-receptor complex, where it is ubiquitinated, and activates transcription factor NF-κB and mitogen-activated protein kinases (MAPK). Smac-mimetics (SM) is a group of drugs that block RIPK1 ubiquitination and shifts RIPK1 to activation of apoptosis or necroptosis...

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3 -knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response...

ABIN-1, also called TNIP1, is an ubiquitin-binding protein that serves an important role in suppressing RIPK1-independent apoptosis, necroptosis, and NF-κB activation. However, the involvement of ABIN-1 in the regulation of RIPK1-dependent apoptosis (RDA) is unknown. In this study, we found that poly(I:C) + TAK1 inhibitor 5Z-7-oxozeaenol (P5) concurrently induces RDA and necroptosis in Abin-1-/- , but not in Abin-1+/+ mouse embryonic fibroblasts (MEFs). Upon P5 stimulation, cells initially die by necroptosis and subsequently by RDA...

Apoptosis resistance worsens treatment response in cancer and is associated with poor prognosis. Inhibition of anti-apoptotic proteins can restore cell death and improve treatment efficacy. cIAP1, cIAP2, and XIAP belong to the inhibitor of apoptosis protein (IAP) family and block apoptosis. Targeting IAPs with peptides or peptidomimetics mimicking the IAP-antagonizing activity of the cell's endogenous IAP antagonist SMAC (SMAC mimetics) showed promising results and fueled development of novel compounds. ASTX660 belongs to the recently introduced class of non-peptidomimetic IAP antagonists and successfully completed phase I clinical trials...

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations...

Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy...

Colorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells...

Liver kinase B1 ( LKB1/STK11 ) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerabilities of this subgroup of tumors exploitable to design specific therapies we screened an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1. Among eight hit compounds, Birinapant, an inhibitor of the Inhibitor of Apoptosis Proteins (IAPs), was the most active compound in LKB1-deleted clone only compared to its LKB1 WT counterpart...

Caspase 8 (CASP8) is one of the most frequently mutated genes in head and neck squamous carcinomas (HNSCC), and CASP8 mutations are associated with poor survival. The distribution of these mutations in HNSCC suggests that they are likely to be inactivating. Inhibition of CASP8 has been reported to sensitize cancer cells to necroptosis, a regulated cell death mechanism. Here, we show that knockdown of CASP8 renders HNSCCs susceptible to necroptosis by a second mitochondria-derived activator of caspase (SMAC) mimetic, Birinapant, in combination with pan-caspase inhibitors zVAD FMK or Emricasan and radiation...

BACKGROUND: For most patients, pancreatic adenocarcinoma responds poorly to treatment, and novel therapeutic approaches are needed. Standard-of-care paclitaxel (PTX), combined with birinapant (BRP), a bivalent mimetic of the apoptosis antagonist SMAC (second mitochondria-derived activator of caspases), exerts synergistic killing of PANC-1 human pancreatic adenocarcinoma cells. METHODS: To investigate potential mechanisms underlying this synergistic pharmacodynamic interaction, data capturing PANC-1 cell growth, apoptosis kinetics, and cell cycle distribution were integrated with high-quality IonStar-generated proteomic data capturing changes in the relative abundance of more than 3300 proteins as the cells responded to the two drugs, alone and combined...