Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Juric, D and Castel, P and Griffith, M and Griffith, OL and Won, HH and Ellis, H and Ebbesen, SH and Ainscough, BJ and Ramu, A and Iyer, G and Shah, RH and Huynh, T and Mino-Kenudson, M and Sgroi, D and Isakoff, S and Thabet, A and Elamine, L and Solit, DB and Lowe, SW and Quadt, C and Peters, M and Derti, A and Schegel, R and Huang, A and Mardis, ER and Berger, MF and Baselga, J and Scaltriti, M (2014) Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature.

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)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

Item Type: Article
Additional Information: NIBR author: Derti, A institute: NIBR contributor address: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USAHuman Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA1] 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, USA1] 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, USA1] 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, USAHuman Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USACancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USAThe Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USAThe Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA1] 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, USAHuman Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USAMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USAMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USAMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USAMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USAMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USAMassachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA1] 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, USA1] 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, USANovartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, SwitzerlandNovartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, SwitzerlandOncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USAOncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USAOncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA1] 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, USA1] 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, USA1] 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, USAHuman Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/24924

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.