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


Authors: Juric, D.; Castel, P.; Griffith, M.; Griffith, O. L.; Won, H. H.; Ellis, H.; Ebbesen, S. H.; Ainscough, B. J.; Ramu, A.; Iyer, G.; Shah, R. H.; Huynh, T.; Mino-Kenudson, M.; Sgroi, D.; Isakoff, S.; Thabet, A.; Elamine, L.; Solit, D. B.; Lowe, S. W.; Quadt, C.; Peters, M.; Derti, A.; Schegel, R.; Huang, A.; Mardis, E. R.; Berger, M. F.; Baselga, J.; Scaltriti, M.
Article Title: Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor
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 p110α 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. © 2015 Macmillan Publishers Limited. All rights reserved.
Journal Title: Nature
Volume: 518
Issue: 7538
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2015-02-12
Start Page: 240
End Page: 244
Language: English
DOI: 10.1038/nature13948
PROVIDER: scopus
PMCID: PMC4326538
PUBMED: 25409150
DOI/URL:
Notes: Export Date: 4 May 2015 -- Source: Scopus
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MSK Authors
  1. David Solit
    431 Solit
  2. Gopakumar Vasudeva Iyer
    125 Iyer
  3. Michael Forman Berger
    380 Berger
  4. Scott W Lowe
    145 Lowe
  5. Helen Hyeong-Eun Won
    79 Won
  6. Ronak Hasmukh Shah
    43 Shah
  7. Pau Castel
    19 Castel
  8. Jose T Baselga
    395 Baselga
  9. Haley Lynn Ellis
    7 Ellis