Publication Date:
2014-11-20
Description:
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)Kalpha) mutation. The patient was treated with the PI(3)Kalpha 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 p110beta 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)Kalpha inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Juric, Dejan -- Castel, Pau -- Griffith, Malachi -- Griffith, Obi L -- Won, Helen H -- Ellis, Haley -- Ebbesen, Saya H -- Ainscough, Benjamin J -- Ramu, Avinash -- Iyer, Gopa -- Shah, Ronak H -- Huynh, Tiffany -- Mino-Kenudson, Mari -- Sgroi, Dennis -- Isakoff, Steven -- Thabet, Ashraf -- Elamine, Leila -- Solit, David B -- Lowe, Scott W -- Quadt, Cornelia -- Peters, Malte -- Derti, Adnan -- Schegel, Robert -- Huang, Alan -- Mardis, Elaine R -- Berger, Michael F -- Baselga, Jose -- Scaltriti, Maurizio -- CA105388/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- T32 CA-71345-15/CA/NCI NIH HHS/ -- T32 CA071345/CA/NCI NIH HHS/ -- T32 GM065094/GM/NIGMS NIH HHS/ -- U01 CA168409/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 12;518(7538):240-4. doi: 10.1038/nature13948. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA. ; Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; 1] Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [3] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; 1] Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [2] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [3] Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; 1] Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; 1] Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Division of Genitourinary Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Howard Hughes Medical Institute, Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland. ; Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. ; 1] Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [3] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [4] Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; 1] Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409150" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Animals
;
Breast Neoplasms/*drug therapy/*genetics/metabolism/pathology
;
Drug Resistance, Neoplasm/drug effects/*genetics
;
Female
;
Humans
;
Loss of Heterozygosity/drug effects/genetics
;
Mice
;
Mice, Nude
;
PTEN Phosphohydrolase/*deficiency/*genetics/metabolism
;
Phosphatidylinositol 3-Kinases/*antagonists & inhibitors
;
Thiazoles/*pharmacology/therapeutic use
;
Xenograft Model Antitumor Assays
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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