PRC1 sustains the integrity of neural fate in the absence of PRC2 function.

Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation.

De Novo DNA Methylation: Marking the Path from Stem Cell to Neural Fate.

DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells.

PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes.

The heterogeneous nature of mammalian PRC1 complexes has hindered our understanding of their biological functions. Here, we present a comprehensive proteomic and genomic analysis that uncovered six major groups of PRC1 complexes, each containing a distinct PCGF subunit, a RING1A/B ubiquitin ligase, and a unique set of associated polypeptides. These PRC1 complexes differ in their genomic localization, and only a small subset colocalize with H3K27me3.

AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.

Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor.

Genetic predictors of MEK dependence in non-small cell lung cancer.

Hyperactivated extracellular signal-regulated kinase (ERK) signaling is common in human cancer and is often the result of activating mutations in BRAF, RAS, and upstream receptor tyrosine kinases. To characterize the mitogen-activated protein kinase/ERK kinase (MEK)/ERK dependence of lung cancers harboring BRAF kinase domain mutations, we screened a large panel of human lung cancer cell lines (n = 87) and tumors (n = 916) for BRAF mutations. We found that non-small cell lung cancers (NSCLC) cells with both V600E and non-V600E BRAF mutations were selectively sensitive to MEK inhibition compared with those harboring mutations in epidermal growth factor receptor (EGFR), KRAS, or ALK and ROS kinase fusions.

Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel.

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients.

SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers.

Purpose: The heat shock protein 90 (Hsp90) chaperone plays an important role in transformation by regulating the conformational maturation and stability of oncogenic kinases and transcription factors. Ansamycins, such as 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), inhibit Hsp90 function; induce the degradation of Hsp90 client proteins such as HER2, and have shown activity in early clinical trials. However, the utility of these drugs has been limited by their hepatotoxicity, poor solubility, and poorly tolerated formulations.

Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors.

Background: The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer.

Methodology/principal Findings: To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M) alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor.

Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors.

Activating mutations in the epidermal growth factor receptor (EGFR), localized in the activation loop within the kinase domain, have been discovered in non-small cell lung cancers (NSCLC). Most of these mutants are exquisitely sensitive to EGFR tyrosine kinase inhibitors, suggesting that they generate receptor dependence in the cancers that express them. 32D cells stably expressing EGFR-L861Q and EGFR-L858R but not wild-type EGFR exhibited ligand-independent receptor phosphorylation and viability.

BRAF mutation predicts sensitivity to MEK inhibition.

The kinase pathway comprising RAS, RAF, mitogen-activated protein kinase kinase (MEK) and extracellular signal regulated kinase (ERK) is activated in most human tumours, often through gain-of-function mutations of RAS and RAF family members. Using small-molecule inhibitors of MEK and an integrated genetic and pharmacologic analysis, we find that mutation of BRAF is associated with enhanced and selective sensitivity to MEK inhibition when compared to either 'wild-type' cells or cells harbouring a RAS mutation. This MEK dependency was observed in BRAF mutant cells regardless of tissue lineage, and correlated with both downregulation of cyclin D1 protein expression and the induction of G1 arrest.