Functional characterization of somatic mutations in cancer using network-based inference of protein activity

Alvarez, Mariano J.; Shen, Yao; Giorgi, Federico M.; Lachmann, Alexander; Ding, Bin; Ye, B Hilda; Califano, Andrea

doi:10.1038/ng.3593

Cited by 745 publications

(1,113 citation statements)

References 61 publications

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“…RNA and protein expression and particularly the amounts of post-translationally modified and functional proteins are frequently weakly correlated (50). Although it may be possible to impute protein function by quantifying downstream RNA master regulators (51), analysis of proteins and protein function may provide a more direct assessment. Thus, analysis of protein function may provide a more efficient approach to identify adaptive responses.…”

Section: Discussionmentioning

confidence: 99%

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

et al. 2017

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Mutant RAS has remained recalcitrant to targeted therapy efforts. Here we demonstrate that combined treatment with poly ADP ribose polymerase (PARP) inhibitors and MEK inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with: 1) induction of BIM-mediated apoptosis, 2) decrease in expression of components of the homologous recombination DNA repair pathway, 3) decrease in homologous recombination DNA damage repair capacity, 4) decrease in DNA damage checkpoint activity, 5) increase in PARP inhibitor-induced DNA damage, 6) decrease in vascularity which could increase PARP inhibitor efficacy by inducing hypoxia, and 7) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

et al. 2017

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“…Candidate MR proteins for each of the high-risk subtypes were then prioritized based on the enrichment of their transcriptional target genes in the subtype-specific signature, using the VIPER algorithm (19). Specifically, we used signatures representing the differential gene expression of each high-risk subtype compared to stage 1 samples (good-prognosis), which showed significant overlap between the TARGET and NRC datasets (Supplementary Figure S3B).…”

Section: Resultsmentioning

confidence: 99%

“…Cell lines harboring MYCN amplifications as well as having high MYCN expression and signature activity (Supplementary Figure S4 A–D) were selected as candidate representatives of the MYCNA subtype and further refined based on the activity of the top 25 VIPER-inferred MRs selected for validation (Supplementary Figure S4E) (19). Most MYCN Amp cell lines showed high activity of these proteins, with BE2 identified as the model with the most statistically significant MR-activity match by enrichment analysis ( P = 3.7E-24; Supplementary Figure S4E).…”

Section: Resultsmentioning

confidence: 99%

“…Critically, aberrant activity of tumor checkpoint MRs arises from one or more genetic alterations in their upstream pathways (14, 17), thus providing a rationale for the heterogeneous mutational landscape of tumors with highly similar transcriptional states (15). MR proteins have been shown to represent critical molecular tumor vulnerabilities that can be effectively targeted pharmacologically in several human malignancies (10, 11, 16, 18, 19), thus providing novel therapeutic opportunities. Here, we sought to interrogate regulatory networks of high-risk neuroblastomas to identify and validate MR proteins representing highly conserved, tumor-specific vulnerabilities for specific subtypes of this malignancy.…”

Section: Introductionmentioning

confidence: 99%

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Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

et al. 2018

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High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10–protein transcriptional module – centered around a TEAD4 ↔ MYCN positive-feedback loop – emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.

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“…Theoretically, these master regulator proteins play a central role in the transcriptional architecture of the tumor by canalizing the upstream effects of oncogenic driver mutations and other aberrant signals to the rest of the network downstream. Targeted therapies against these master regulator proteins could lead to an efficient treatment of the disease [54,55]. …”

Section: Drug Repositioningmentioning

confidence: 99%

Pancreas Cancer Precision Treatment Using Avatar Mice from a Bioinformatics Perspective

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Piñeiro-Yáñez²,

Tejero³

et al. 2017

Public Health Genomics

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death among solid malignancies. Unfortunately, PDAC lethality has not substantially decreased over the past 20 years. This aggressiveness is related to the genomic complexity and heterogeneity of PDAC, but also to the absence of an effective screening for the detection of early-stage tumors and a lack of efficient therapeutic options. Therefore, there is an urgent need to improve the arsenal of anti-PDAC drugs for an effective treatment of these patients. Patient-derived xenograft (PDX) mouse models represent a promising strategy to personalize PDAC treatment, offering a bench testing of candidate treatments and helping to select empirical treatments in PDAC patients with no therapeutic targets. Moreover, bioinformatics-based approaches have the potential to offer systematic insights into PDAC etiology predicting putatively actionable tumor-specific genomic alterations, identifying novel biomarkers and generating disease-associated gene expression signatures. This review focuses on recent efforts to individualize PDAC treatments using PDX models. Additionally, we discuss the current understanding of the PDAC genomic landscape and the putative druggable targets derived from mutational studies. PDAC molecular subclassifications and gene expression profiling studies are reviewed as well. Finally, latest bioinformatics methodologies based on somatic variant detection and prioritization, in silico drug response prediction, and drug repositioning to improve the treatment of advanced PDAC tumors are also covered.

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Functional characterization of somatic mutations in cancer using network-based inference of protein activity

Cited by 745 publications

References 61 publications

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

Pancreas Cancer Precision Treatment Using Avatar Mice from a Bioinformatics Perspective

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