Dataset Information

Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.

ABSTRACT: Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter-screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB-deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC.

SUBMITTER: Witkiewicz AK

PROVIDER: S-EPMC5967622 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.

Witkiewicz Agnieszka K AK Chung Sejin S Brough Rachel R Vail Paris P Franco Jorge J Lord Christopher J CJ Knudsen Erik S ES

Cell reports 20180101 5

Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK ...[more]

PMID: 29386107

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Project description:PurposeStemming from a myriad of genetic and epigenetic alterations, triple-negative breast cancer (TNBC) is tied to poor clinical outcomes and aspires for individualized therapies. Here we investigated the therapeutic potential of co-inhibiting integrin-dependent signaling pathway and BRD4, a transcriptional and epigenetic mediator, for TNBC.MethodsTwo independent patient cohorts were subjected to bioinformatic and IHC examination for clinical association of candidate cancer drivers. The efficacy and biological bases for co-targeting these drivers were interrogated using cancer cell lines, a protein kinase array, chemical inhibitors, RNAi/CRISPR/Cas9 approaches, and a 4 T1-Balb/c xenograft model.ResultsWe found that amplification of the chromosome 8q24 region occurred in nearly 20% of TNBC tumors, and that it coincided with co-upregulation or amplification of c-Myc and FAK, a key effector of integrin-dependent signaling. This co-upregulation at the mRNA or protein level correlated with a poor patient survival (p < 0.0109 or p < 0.0402, respectively). Furthermore, we found that 14 TNBC cell lines exhibited high vulnerabilities to the combination of JQ1 and VS-6063, potent pharmacological antagonists of the BRD4/c-Myc and integrin/FAK-dependent pathways, respectively. We also observed a cooperative inhibitory effect of JQ1 and VS-6063 on tumor growth and infiltration of Ly6G+ myeloid-derived suppressor cells in vivo. Finally, we found that JQ1 and VS-6063 cooperatively induced apoptotic cell death by altering XIAP, Bcl2/Bcl-xl and Bim levels, impairing c-Src/p130Cas-, PI3K/Akt- and RelA-associated signaling, and were linked to EMT-inducing transcription factor Snail- and Slug-dependent regulation.ConclusionBased on our results, we conclude that the BRD4/c-Myc- and integrin/FAK-dependent pathways act in concert to promote breast cancer cell survival and poor clinical outcomes. As such, they represent promising targets for a synthetic lethal-type of therapy against TNBC.

Dataset Information

Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.

Publications

Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.

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