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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 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.

journal_name

Nature

journal_title

Nature

authors

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,Scheg

doi

10.1038/nature13948

subject

Has Abstract

pub_date

2015-02-12 00:00:00

pages

240-4

issue

7538

eissn

0028-0836

issn

1476-4687

pii

nature13948

journal_volume

518

pub_type

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