↓ Skip to main content

Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.

Overview of attention for article published in Nature, November 2014
Altmetric Badge

About this Attention Score

  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (96th percentile)
  • Average Attention Score compared to outputs of the same age and source

Mentioned by

news
1 news outlet
blogs
2 blogs
twitter
42 tweeters
peer_reviews
1 peer review site
facebook
3 Facebook pages

Readers on

mendeley
195 Mendeley
citeulike
5 CiteULike
Title
Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor.
Published in
Nature, November 2014
DOI 10.1038/nature13948
Pubmed ID
Authors

Dejan Juric, Pau Castel, Malachi Griffith, Obi L. Griffith, Helen H. Won, Haley Ellis, Saya H. Ebbesen, Benjamin J. Ainscough, Avinash Ramu, Gopa Iyer, Ronak H. Shah, Tiffany Huynh, Mari Mino-Kenudson, Dennis Sgroi, Steven Isakoff, Ashraf Thabet, Leila Elamine, David B. Solit, Scott W. Lowe, Cornelia Quadt, Malte Peters, Adnan Derti, Robert Schegel, Alan Huang, Elaine R. Mardis, Michael F. Berger, José Baselga, Maurizio Scaltriti, Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H, Ebbesen SH, Ainscough BJ, Ramu A, Iyer G, Shah RH, Huynh T, Mino-Kenudson M, Sgroi D, Isakoff S, Thabet A, Elamine L, Solit DB, Lowe SW, Quadt C, Peters M, Derti A, Schegel R, Huang A, Mardis ER, Berger MF, Baselga J, Scaltriti M

Abstract

Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

Twitter Demographics

The data shown below were collected from the profiles of 42 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 195 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United States 8 4%
United Kingdom 3 2%
Germany 1 <1%
Australia 1 <1%
France 1 <1%
Italy 1 <1%
South Africa 1 <1%
Denmark 1 <1%
Belgium 1 <1%
Other 2 1%
Unknown 175 90%

Demographic breakdown

Readers by professional status Count As %
Researcher 77 39%
Student > Ph. D. Student 46 24%
Other 17 9%
Student > Master 14 7%
Student > Doctoral Student 11 6%
Other 30 15%
Readers by discipline Count As %
Agricultural and Biological Sciences 81 42%
Medicine and Dentistry 43 22%
Biochemistry, Genetics and Molecular Biology 37 19%
Unspecified 7 4%
Chemistry 6 3%
Other 21 11%

Attention Score in Context

This research output has an Altmetric Attention Score of 45. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 April 2017.
All research outputs
#215,815
of 8,446,126 outputs
Outputs from Nature
#13,334
of 48,180 outputs
Outputs of similar age
#7,080
of 232,263 outputs
Outputs of similar age from Nature
#450
of 902 outputs
Altmetric has tracked 8,446,126 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 97th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 48,180 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 75.1. This one has gotten more attention than average, scoring higher than 72% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 232,263 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 96% of its contemporaries.
We're also able to compare this research output to 902 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 50% of its contemporaries.