Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy

ABSTRACTMost patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involvesynthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (therescuer). Here we perform a genome-wide prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.

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Clinical Relevance of Plasma DNA Methylation in Colorectal Cancer Patients Identified by Using a Genome-Wide High-Resolution Array

Annals of Surgical Oncology ◽

10.1245/s10434-014-4277-2 ◽

2014 ◽

Vol 22 (S3) ◽

pp. 1419-1427 ◽

Cited By ~ 26

Author(s):

Pei-Ching Lin ◽

Jen-Kou Lin ◽

Chien-Hsing Lin ◽

Hung-Hsin Lin ◽

Shung-Haur Yang ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

High Resolution ◽

Cancer Patients ◽

Clinical Relevance ◽

Plasma Dna ◽

Genome Wide ◽

A Genome ◽

Colorectal Cancer Patients

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A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells

Cancer Cell ◽

10.1016/j.ccr.2013.07.008 ◽

2013 ◽

Vol 24 (2) ◽

pp. 182-196 ◽

Cited By ~ 99

Author(s):

Fabio Petrocca ◽

Gabriel Altschuler ◽

Shen Mynn Tan ◽

Marc L. Mendillo ◽

Haoheng Yan ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Sirna Screen ◽

Genome Wide ◽

A Genome

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A genome-wide transcriptome profiling reveals the early molecular events during callus initiation in Arabidopsis multiple organs

Genomics ◽

10.1016/j.ygeno.2012.05.013 ◽

2012 ◽

Vol 100 (2) ◽

pp. 116-124 ◽

Cited By ~ 37

Author(s):

Ke Xu ◽

Jing Liu ◽

Mingzhu Fan ◽

Wei Xin ◽

Yuxin Hu ◽

...

Keyword(s):

Transcriptome Profiling ◽

Multiple Organs ◽

Molecular Events ◽

Genome Wide ◽

A Genome ◽

Callus Initiation

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A genome-wide RNA interference screen identifies new regulators of androgen receptor function in prostate cancer cells

Genome Research ◽

10.1101/gr.144774.112 ◽

2013 ◽

Vol 23 (4) ◽

pp. 581-591 ◽

Cited By ~ 22

Author(s):

K. Imberg-Kazdan ◽

S. Ha ◽

A. Greenfield ◽

C. S. Poultney ◽

R. Bonneau ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Rna Interference ◽

Cancer Cells ◽

Receptor Function ◽

Prostate Cancer Cells ◽

Genome Wide ◽

A Genome ◽

Androgen Receptor Function

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A genome-wide approach to link genotype to clinical outcome by simultaneously utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.e12074 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. e12074-e12074

Author(s):

Balazs Gyorffy ◽

Mate Kormos ◽

Lorinc Pongor

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Clinical Outcome ◽

Cancer Patients ◽

Next Generation ◽

Breast Cancer Patients ◽

Chip Data ◽

Genome Wide ◽

A Genome ◽

Generation Sequencing

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A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients

Genome Medicine ◽

10.1186/s13073-015-0228-1 ◽

2015 ◽

Vol 7 (1) ◽

Cited By ~ 36

Author(s):

Lőrinc Pongor ◽

Máté Kormos ◽

Christos Hatzis ◽

Lajos Pusztai ◽

András Szabó ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Clinical Outcome ◽

Cancer Patients ◽

Next Generation ◽

Breast Cancer Patients ◽

Chip Data ◽

Genome Wide ◽

A Genome ◽

Generation Sequencing

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KLF4 binding is involved in the organization and regulation of 3D enhancer networks during acquisition and maintenance of pluripotency

10.1101/382473 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dafne Campigli Di Giammartino ◽

Andreas Kloetgen ◽

Alexander Polyzos ◽

Yiyuan Liu ◽

Daleum Kim ◽

...

Keyword(s):

Cell Fate ◽

Binding Sites ◽

Target Gene ◽

Embryonic Fibroblasts ◽

Molecular Events ◽

Genome Wide ◽

A Genome ◽

Integrative View ◽

Transcriptional Changes ◽

Complex Activities

SUMMARYCell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is strikingly exemplified by reprogramming somatic cells to pluripotent stem cells (PSCs) via expression of OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their target gene loci in a temporal manner remains incompletely understood. Here, using KLF4 as a paradigm, we provide the first TF-centric view of chromatin reorganization and its association to 3D enhancer rewiring and transcriptional changes of linked genes during reprogramming of mouse embryonic fibroblasts (MEFs) to PSCs. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in the connectivity of enhancers, while disruption of individual KLF4 binding sites from PSC-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying TF during a controlled cell fate transition and offers novel insights into the order and nature of molecular events that follow TF binding.

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