RESUMEN
Targeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance antitumor immunity and augment cancer immunotherapies. By screening a small-molecule library of epigenetics-based therapeutics, BET (bromo- and extra-terminal domain) inhibitors (BETi) were identified as agents that sensitize tumor cells to the antitumor activity of CD8+ T cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the proinflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-κB target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of prosurvival NF-κB signaling by BETi led to unrestrained TNF-mediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific antibodies (TCB) or immune-checkpoint blockade increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune-oncology agents.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Nucleares/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Animales , Apoptosis/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.
Asunto(s)
Linaje de la Célula , Plasticidad de la Célula , Neoplasias Pulmonares/patología , Tumores Neuroendocrinos/patología , Fenotipo , Neoplasias de la Próstata/patología , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/terapia , Masculino , Tumores Neuroendocrinos/terapia , Neoplasias de la Próstata/terapiaRESUMEN
Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data point to a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may also be relevant for other solid tumors.
Asunto(s)
Linaje de la Célula , Plasticidad de la Célula , Proteínas Cromosómicas no Histona/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Factores de Transcripción/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Línea Celular Tumoral , Estudios de Cohortes , ADN Helicasas/genética , ADN Helicasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Masculino , Modelos Biológicos , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/genética , Subunidades de Proteína/metabolismo , Factores de Transcripción/genética , Transcriptoma/genéticaRESUMEN
An outgrowth of therapy-resistant prostate cancers (PCa) with enhanced metastatic potential may be triggered by inhibitors of androgen receptor (AR) signaling, often via epigenetic rewiring. In this issue of Cancer Cell, Yuan et al. demonstrate how SETD2 integrates EZH2 and AMPK signaling pathways to keep PCa metastasis in check.
Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Proteínas Quinasas Activadas por AMP , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismoRESUMEN
Proteolysis targeting chimeras are bifunctional small molecules capable of recruiting a target protein of interest to an E3 ubiquitin ligase that facilitates target ubiquitination followed by proteasome-mediated degradation. The first molecules acting on this novel therapeutic paradigm have just entered clinical testing. Here, by using Bromodomain Containing 4 (BRD4) degraders engaging cereblon and Von Hippel-Lindau E3 ligases, we investigated key determinants of resistance to this new mode of action. A loss-of-function screen for genes required for BRD4 degradation revealed strong dependence on the E2 and E3 ubiquitin ligases as well as for members of the COP9 signalosome complex for both cereblon- and Von Hippel-Lindau-engaging BRD4 degraders. Cancer cell lines raised to resist BRD4 degraders manifested a degrader-specific mechanism of resistance, resulting from the loss of components of the ubiquitin proteasome system. In addition, degrader profiling in a cancer cell line panel revealed a differential pattern of activity of Von Hippel-Lindau- and cereblon-based degraders, highlighting the need for the identification of degradation-predictive biomarkers enabling effective patient stratification.
