Synthetic lethality of mRNA quality control complexes in cancer.

Synthetic lethality exploits the genetic vulnerabilities of cancer cells to enable a targeted, precision approach to treat cancer. Over the past 15 years, synthetic lethal cancer target discovery approaches have led to clinical successes of PARP inhibitors and ushered several next-generation therapeutic targets such as WRN, USP1, PKMYT1, POLQ and PRMT5 into the clinic. Here we identify, in human cancer, a novel synthetic lethal interaction between the PELO-HBS1L and SKI complexes of the mRNA quality control pathway.

MYC Family Amplification Dictates Sensitivity to BET Bromodomain Protein Inhibitor Mivebresib (ABBV075) in Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN but not MYCL1 or non-amplified MYC cell lines exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor mivebresib (ABBV075).

Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition.

Selective Inhibition of the Second Bromodomain of BET Family Proteins Results in Robust Antitumor Activity in Preclinical Models of Acute Myeloid Leukemia.

Dual bromodomain BET inhibitors that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4, and BRDT have displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of gastrointestinal toxicity, have presented as dose-limiting adverse events that may have prevented escalation to higher dose levels required for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain of the four BET family proteins.

Toll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic target.

The gene fusion and subsequent overexpression of the ERG transcription factor occurs in ∼50% of prostate tumors, making it the most common abnormality of the prostate cancer genome. While ERG has been shown to drive tumor progression and cancer-related phenotypes, as a transcription factor it is difficult to target therapeutically. Using a genetic screen, we identified the toll-like receptor 4 (TLR4) signaling pathway as important for ERG function in prostate cells.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi.

ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase.

Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment.

Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2.

Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types.

Genome-Wide Analysis of RAS/ERK Signaling Targets.

Identifying gene expression changes mediated by signaling pathways is necessary to determine mechanisms that cause phenotypic change. Recent advances in next-generation sequencing and informatic pipelines have streamlined the ability for laboratories to create and analyze transcriptomic data. Here, we describe the preparation of samples and transcriptomic analysis in order to determine gene expression programs regulated by RAS/ERK signaling.

An Interaction with Ewing's Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer.

More than 50% of prostate tumors have a chromosomal rearrangement resulting in aberrant expression of an oncogenic ETS family transcription factor. However, mechanisms that differentiate the function of oncogenic ETS factors expressed in prostate tumors from non-oncogenic ETS factors expressed in normal prostate are unknown. Here, we find that four oncogenic ETS (ERG, ETV1, ETV4, and ETV5), and no other ETS, interact with the Ewing's sarcoma breakpoint protein, EWS.

Extracellular signal-regulated kinase signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration.

JUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c-JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear.

ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells.

The RAS/ERK pathway is commonly activated in carcinomas and promotes oncogenesis by altering transcriptional programs. However, the array of cis-regulatory elements and trans-acting factors that mediate these transcriptional changes is still unclear. Our genome-wide analysis determined that a sequence consisting of neighboring ETS and AP-1 transcription factor binding sites is enriched near cell migration genes activated by RAS/ERK signaling in epithelial cells.