RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Serra, Violeta; Eichhorn, Pieter J.A.; García-García, Celina; Ibrahim, Yasir H.; Prudkin, Ludmila; Sánchez, Gertrudis; Rodríguez, Olga; Antón, Pilar; Parra, Josep-Lluís; Marlow, Sara; Scaltriti, Maurizio; Peréz-García, José Manuel; Prat, Aleix; Arribas, Joaquı́n; Hahn, William C.; Kim, So Young; Baselga, J.

doi:10.1172/jci66343

Cited by 112 publications

(81 citation statements)

References 70 publications

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“…In the case of downstream PI3K activation, studies in a mouse mammary tumor model engineered to express an activated PIK3CA allele (H1047R) demonstrated that activation of the Myc oncogene rendered these tumors resistant to selective PI3K inhibitors (10,11). Gene amplification of the downstream effector, eukaryotic translation initiation factor 4E (eIF4E), and overexpression of the ribosomal protein S6 kinase, 90kDa, polypeptides 3 and 4 (RSK3 and RSK4) have also been shown to confer resistance to PI3K inhibitors (11,12). Mechanisms acting upstream of PI3K have also been described, including dysregulation of the receptor tyrosine kinases AXL and c-MET, and overexpression of the EGFR ligand amphiregulin (AREG) in the background of PTEN loss (10,13,14).…”

Section: Introductionmentioning

confidence: 99%

Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β

Nakanishi¹,

Walter²,

Spoerke³

et al. 2016

Cancer Research

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Activation of the PI3K pathway occurs commonly in a wide variety of cancers. Experience with other successful targeted agents suggests that clinical resistance is likely to arise and may reduce the durability of clinical benefit. Here, we sought to understand mechanisms underlying resistance to PI3K inhibition in PTEN-deficient cancers. We generated cell lines resistant to the pan-PI3K inhibitor GDC-0941 from parental PTEN-null breast cancer cell lines and identified a novel PIK3CB D1067Y mutation in both cell lines that was recurrent in cancer patients. Stable expression of mutant PIK3CB variants conferred resistance to PI3K inhibition that could be overcome by downstream AKT or mTORC1/2 inhibitors. Furthermore, we show that the p110b D1067Y mutant was highly activated and induced PIP3 levels at the cell membrane, subsequently promoting the localization and activation of AKT and PDK1 at the membrane and driving PI3K signaling to a level that could withstand treatment with proximal inhibitors. Finally, we demonstrate that the PIK3CB D1067Y mutant behaved as an oncogene and transformed normal cells, an activity that was enhanced by PTEN depletion. Collectively, these novel preclinical and clinical findings implicate the acquisition of activating PIK3CB D1067 mutations as an important event underlying the resistance of cancer cells to selective PI3K inhibitors.

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Section: Introductionmentioning

confidence: 99%

Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β

Nakanishi¹,

Walter²,

Spoerke³

et al. 2016

Cancer Research

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“…Depending on the cell type, AA and other long fatty acyl chain lipids can be converted through enzymatic and nonenzymatic reactions into multiple species that can be grouped into two main classes: (1) PGs derived from the initial production of means to assess compound attributes and "drug-likeness" ( 7 ). With the increasing availability of large pharmacological databases ( 8,9 ), in silico prediction algorithms are starting to provide a foundation for the analysis of interaction networks involving drugs, targets, and antitargets. Complementing in silico approaches, advances in analytical chemistry, particularly in the fi eld of MS, are enabling larger scale quantifi cation of multiple analytes with unprecedented specifi city, sensitivity, and accuracy.…”

Section: Metabolic Phenotypingmentioning

confidence: 99%

Phenotyping drug polypharmacology via eicosanoid profiling of blood

Song

Liu

Rao

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org status to fi nd the right drug match. Several pharmaceutical and biotechnology companies are placing substantial effort in the development of such tailored therapeutics, with the prospects of signifi cantly improved clinical outcomes: effi cacy associated with reductions in adverse events ( 1,2 ).While precision medicine already shows high potential for the discovery of highly effi cacious, safer medicines, targeted drug development requires in-depth understanding of the mechanism of action of experimental compounds, as well as robust systems for accurate profi ling (and prediction) of therapeutic response. The systematic analysis of drugs that interact with more than one molecular target offers an opportunity to dissect the complexities of drug action and constitutes the fi rst step for the construction of computational models to predict polypharmacology ( 3, 4 ). Advances in omics platforms over the past decade have enabled early exploration of global physiological perturbations (genome, proteome, metabolome, epigenome, and lipidome) in health and disease, thus ushering in the era of systems biology. Several approaches drawing from this emerging discipline have been utilized to build drugtarget networks for complex diseases, involving multiple drugs acting on distinct targets. Those efforts have aided in the formulation of combinatorial therapy hypotheses ( 5, 6 ). A less desirable, yet central aspect to polypharmacology is the ever-present off-target effects. One major reason for deprioritization of candidate drugs is the discovery of toxicities, often during late preclinical profi ling and clinical development stages. Emerging computational methodologies are starting to provide more effi cient Abstract It is widely accepted that small-molecule drugs, despite their selectivity at primary targets, exert pharmacological effects (and safety liabilities) through a multiplicity of pathways. As such, it has proved extremely difficult to experimentally assess polypharmacology in an agnostic fashion. Profi ling of metabolites produced as part of physiological responses to pharmacological stimuli provides a unique opportunity to explore drug pharmacology. A total of 122 eicosanoid lipids in human whole blood were monitored from 10 different donors upon stimulation with several inducers of immunological responses and treatment with modulators of prostaglandin (PG) and leukotriene biosynthesis, including clinical and investigational molecules. Such analysis revealed differentiation between drugs nominally targeting different eicosanoid biosynthetic enzymes, or even those designed to target the same enzyme. Profi led agents, some of them marketed products, affect eicosanoid biosynthesis in ways that cannot be predicted from information on their intended targets. As an example, we used this platform to discriminate drugs based on their ability to silence PG biosynthesis in response to bacterial lipopolysaccharide, resulting in differential pharmacological activity in ...

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“…Note Human RPS6KA6 gene codes for the protein RSK4, a serine-threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al, 1999;Dümmler et al, 2005;Anjum and Blenis, 2008;Serra et al, 2013).…”

Section: Proteinmentioning

confidence: 99%

“…In addition, RSK4 expression enhances breast cancer cell survival upon PI3K/mTOR inhibitors treatment through inhibition of apoptosis and up-regulation of protein translation. Adding MEK-or RSK-specific inhibitors can overcome the RSK4 mediated resistance, thus, combination of RSK and PI3K pathway inhibitors may overcome the resistance mediated by RSK4 in breast cancer (Serra et al, 2013).…”

Section: Breast Cancermentioning

confidence: 99%

“…

AbstractReview on RPS6KA6, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

IdentityOther names: PP90RSK4, RSK4 HGNC (Hugo): RPS6KA6 Location: Xq21.1

DNA/RNA

DescriptionThe human RPS6KA6 gene is located at Xq21, and contains 22 exons that span approximately 75 kb of genomic DNA and are located on cosmids E1, H22 and G9 in a telomeric to centromeric orientation (Yntema et al, 1999;Dümmler et al, 2005;Kantojärvi et al, 2011).

ProteinNote Human RPS6KA6 gene codes for the protein RSK4, a serine-threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al, 1999;Dümmler et al, 2005;Anjum and Blenis, 2008;Serra et al, 2013).The basic structure of the RSK4. The RSK4 protein includes two kinases domains: amino-terminal kinase domain (NTKD) and carboxyl-terminal kinase domain (CTKD), a linker region and amino-and carboxyl-terminal tails.

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confidence: 99%

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RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6)

Liu¹,

Cao²

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Review on RPS6KA6, with data on DNA/RNA, on the protein encoded and where the gene is implicated. IdentityOther names: PP90RSK4, RSK4 HGNC (Hugo): RPS6KA6 Location: Xq21.1 DNA/RNA DescriptionThe human RPS6KA6 gene is located at Xq21, and contains 22 exons that span approximately 75 kb of genomic DNA and are located on cosmids E1, H22 and G9 in a telomeric to centromeric orientation (Yntema et al, 1999;Dümmler et al., 2005;Kantojärvi et al., 2011). ProteinNote Human RPS6KA6 gene codes for the protein RSK4, a serine-threonine kinase with 745 amino acids, also a member of the 90 kDa ribosomal S6 kinase (RSK) family which includes other three members RSK1, RSK2 and RSK3 (Yntema et al., 1999;Dümmler et al., 2005;Anjum and Blenis, 2008;Serra et al., 2013).The basic structure of the RSK4. The RSK4 protein includes two kinases domains: amino-terminal kinase domain (NTKD) and carboxyl-terminal kinase domain (CTKD), a linker region and amino-and carboxyl-terminal tails. The NTKD is responsible for substrate phosphorylation and CTKD regulates sutophosphorylation of the RSK4. The two kinase domains are connected by a linker region which is about 100 amino acids containing essential regulatory domains including hydrophobic and turn motifs, involved in the activation of NTKD. An ERK-docking motif, known also as the D domain, is located in the carboxyl-terminal tail (Dümmler et al., 2005;Anjum and Blenis, 2008;Romeo et al., 2012).

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RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer

Cited by 112 publications

References 70 publications

Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β

Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β

Phenotyping drug polypharmacology via eicosanoid profiling of blood

RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6)

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