Lung cancer is the leading cause of cancer mortality worldwide. Comprehensive genomic profiling of lung cancers revealed their genetic heterogeneity and complexity and identified numerous targetable oncogenic driver alterations. These molecular profiling efforts have made it possible to exploit the potential of molecularly targeted therapies. Selection of patients for targeted therapies is becoming biomarker-driven, where the oncogenic drivers in patient tumors are first identified, and subsequently patients bearing drug-sensitizing genetic aberrations are matched to the appropriate targeted therapy. Success of this design of clinical trials and practice was first demonstrated in EGFR inhibitor trials in lung cancer and has since been incorporated into subsequent targeted therapy trials including ALK-, ROS1-, and BRAF V600E-targeted therapies. In this review we discuss the current landscape of clinically approved and other promising molecularly targeted approaches for the treatment of lung cancers, the challenges with these approaches, and the strategies that could be deployed to overcome these challenges.

Polymerase associated factor 1 complex (Paf1C) broadly influences gene expression by regulating chromatin structure and the recruitment of RNA-processing factors during transcription elongation. The Plus3 domain of the Rtf1 subunit mediates Paf1C recruitment to genes by binding a repeating domain within the elongation factor Spt5 (suppressor of Ty). Here we provide a molecular description of this interaction by reporting the structure of human Rtf1 Plus3 in complex with a phosphorylated Spt5 repeat. We find that Spt5 binding is mediated by an extended surface containing phosphothreonine recognition and hydrophobic interfaces that interact with residues outside the Spt5 motif. Changes within these interfaces diminish binding of Spt5 in vitro and chromatin localization of Rtf1 in vivo. The structure reveals the basis for recognition of the repeat motif of Spt5, a key player in the recruitment of gene regulatory factors to RNA polymerase II.histone modification | scaffold | DSIF | Cdk9 | crystallography

Histone modifications regulate transcription by RNA polymerase II and maintain a balance between active and repressed chromatin states. The conserved Paf1 complex (Paf1C) promotes specific histone modifications during transcription elongation, but the mechanisms by which it facilitates these marks are undefined. We previously identified a 90-amino acid region within the Rtf1 subunit of Paf1C that is necessary for Paf1C-dependent histone modifications in Saccharomyces cerevisiae. Here we show that this histone modification domain (HMD), when expressed as the only source of Rtf1, can promote H3 K4 and K79 methylation and H2B K123 ubiquitylation in yeast. The HMD can restore histone modifications in rtf1Δ cells whether or not it is directed to DNA by a fusion to a DNA binding domain. The HMD can facilitate histone modifications independently of other Paf1C subunits and does not bypass the requirement for Rad6-Bre1. The isolated HMD localizes to chromatin, and this interaction requires residues important for histone modification. When expressed outside the context of fulllength Rtf1, the HMD associates with and causes Paf1C-dependent histone modifications to appear at transcriptionally inactive loci, suggesting that its function has become deregulated. Finally, the Rtf1 HMDs from other species can function in yeast. Our findings suggest a direct and conserved role for Paf1C in coupling histone modifications to transcription elongation.transcription-coupled histone modifications | nucleosome I n eukaryotes, transcription occurs within the context of a restrictive, yet dynamic, chromatin environment. The posttranslational modification of histones represents a major mechanism by which cells control the structure of chromatin. Some modifications of histones include acetylation, methylation, and ubiquitylation. These modifications can alter the structural properties of nucleosomes and serve as specific effectors for the recruitment of proteins that further modify the chromatin template and regulate transcription (1).Monoubiquitylation of histone H2B on lysine (K) 123 in Saccharomyces cerevisiae is a conserved modification that is enriched on active genes but plays roles in both transcriptional repression and activation (2-4). Consistent with a repressive role, H2B monoubiquitylation stabilizes nucleosomes at yeast promoters (5), inhibits the association of the RNA polymerase (pol) II kinase Ctk1 with genes in yeast (6), and interferes with the recruitment of the elongation factor TFIIS to genes in human cells (7). In other studies, H2B monoubiquitylation has been shown to stimulate transcription of chromatin templates (8), promote nucleosome reassembly during transcription elongation (9), and inhibit chromatin compaction (10). H2B monoubiquitylation is also a prerequisite for other histone modifications that mark active genes. Ubiquitylation of H2B K123 by the Rad6-Bre1 ubiquitin conjugase-ligase proteins in yeast (11-13) is required for dimethylation and trimethylation of H3 K4 and K79 by the Set1/COMPASS and Dot1 methy...

eThe integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBP␥:ATF4 heterodimers, but not C/EBP␤:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBP␥ and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBP␤ and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg ؊/؊ mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg ؊/؊ mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBP␥-deficient newborns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant N-acetylcysteine. Cebpg ؊/؊ mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBP␥ as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.A variety of stresses, such as amino acid limitation, protein misfolding in the endoplasmic reticulum (ER), oxidative stress, hypoxia, and intracellular pathogens, activate gene expression programs collectively known as the integrated stress response (ISR) (1). Stress-induced genes are involved in multiple cellular processes that include nutrient uptake, amino acid synthesis, metabolic changes, antioxidant defenses, and cell survival, leading to cell recovery and alleviation of stress. However, prolonged or irresolvable stress can trigger cell death (2).Protein misfolding and ER stress are associated with several diseases, including diabetes and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Huntington's disease (3). The ISR also plays an important role in cancer as tumor cells frequently experience nutrient deprivation, hypoxia, and oxidative stress and require stress response regulators such as the transcription factor (TF) ATF4 to thrive under adverse conditions (4, 5). Elevated levels of reactive oxygen species (ROS) can initiate oncogenesis by causing DNA mutations and genome instability (6). However, recent studies have shown that, once established, tumor cells are reliant on antioxidant pathways for growth and survival (7,8). Moreover, radio-and chemotherapies induce death or senescence of cancer cells partly by increasing ROS. Thus, acquiring a detailed understanding of the pathways and mechanisms that regulate stress response genes may le...