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 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
authors.forename: Pau
authors.initials: P
authors.lastname: Castel
authors.affiliation: 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.
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: 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.
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: 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.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Won
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
authors.forename: Haley
authors.initials: H
authors.lastname: Ellis
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
authors.forename: Saya H
authors.initials: SH
authors.lastname: Ebbesen
authors.affiliation: The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ainscough
authors.affiliation: The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA.
authors.forename: Avinash
authors.initials: A
authors.lastname: Ramu
authors.affiliation: 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.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
authors.forename: Ronak H
authors.initials: RH
authors.lastname: Shah
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Huynh
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Isakoff
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Thabet
authors.affiliation: Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Elamine
authors.affiliation: 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.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: 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.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.affiliation: Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.affiliation: Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Malte
authors.initials: M
authors.lastname: Peters
authors.affiliation: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Adnan
authors.initials: A
authors.lastname: Derti
authors.affiliation: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Schegel
authors.affiliation: Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.affiliation: 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.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
mesh_terms: D000483:Alleles; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C497132:PIK3CB protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human