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Cited by 588PI3K/AKT/mTOR signaling in cancerCancer Genomics and DiagnosticsAdvanced Breast Cancer Therapies

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

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Juric, Dejan, Castel, Pau, Griffith, Malachi, Griffith, Obi L., Won, Helen H., Ellis, Haley, Ebbesen, Saya H., Ainscough, Benjamin J. +20 more·2015·Nature
DOI 10.1038/nature13948PMC PMC4326538
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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.

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  • Studies of pre-treatment and post-treatment samples identify multiple mechanisms of tumor evolution via low-frequency pre-existing mutations that expand after treatment and/or previously undetectable mutations induced by therapy de novo.

    “Studies of pre-treatment and post-treatment samples identify multiple mechanisms of tumor evolution both via low-frequency pre-existing mutations that expand after treatment and/or previously undetectable mutations that are induced by therapy de novo [99,100].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [99]

    The paper’s paired-sample analysis and summary (both labeled Abstract; page unavailable) describe tumor evolution under BYL719 treatment, including distinct PTEN alterations at progression and possible selection of PIK3CA-wild-type clones. They do not establish that low-frequency pre-existing mutations expanded, or that therapy induced previously undetectable mutations de novo. (LLM, conf=0.85)

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  • As tumors metastasize, their genomes significantly change under new selective pressures, altering their treatment sensitivities accordingly.

    “Furthermore, as tumors metastasize, their genomes significantly change under new selective pressures, altering their treatment sensitivities accordingly [99].”

    From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [99]

    The Abstract (page not provided) reports genomic changes in metastatic lesions under selective pressure from PI3Kα-inhibitor treatment, with PTEN loss linked to resistance. It does not establish that metastasis itself generally creates new selective pressures or that tumors broadly change treatment sensitivity as they metastasize; its central finding concerns evolution during therapy in a patient with metastatic breast cancer. (LLM, conf=0.86)

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Research works printed but not linked: 22

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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.
Affiliations
  • Massachusetts General Hospital (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Washington University in St. Louis (US)
  • Novartis (Switzerland) (CH)
Corresponding author
  • Berger, Michael F.
  • Scaltriti, Maurizio
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2014-11-17
Volume
518
Issue
7538
Pages
240-244
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature13948
PMC
PMC4326538
OpenAlex
W2057366353
Cited by
588
References
4
Citations by year
2026: 28 · 2025: 39 · 2024: 37 · 2023: 52 · 2022: 45 · 2021: 75 · 2020: 63 · 2019: 49 · 2018: 44 · 2017: 64 · 2016: 51 · 2015: 34 · 2014: 7
FWCI
21.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Cancer Institute (CA105388, U01CA105388, R01CA190642, U01CA168409, T32 CA-71345-15, P30CA008748, T32CA113275, T32CA071345)
  • National Institute of General Medical Sciences (T32GM065094)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
Keywords
PTEN loss, PIK3CA mutation, alpelisib, metastatic breast cancer, convergent evolution, clonal evolution, tumor heterogeneity, copy number loss, treatment resistance, lung metastasis, targeted therapy, tumor suppressor, PI3K/Akt signaling
MeSH terms
Phosphoinositide-3 Kinase Inhibitors, Alleles, Animals, Breast Neoplasms, Female, Humans, Mice, Nude, Thiazoles, Drug Resistance, Neoplasm, Loss of Heterozygosity, Xenograft Model Antitumor Assays, PTEN Phosphohydrolase, Mice, Class I Phosphatidylinositol 3-Kinases

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