Journal Article

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

Mardis, Elaine R., Quadt, Cornelia, Ellis, Haley, Iyer, Gopa, Scaltriti, Maurizio, Huang, Alan, Juric, Dejan, Peters, Malte, Baselga, José, Solit, David B., Castel, Pau, Ramu, Avinash, Thabet, Ashraf, Huynh, Tiffany, Schegel, Robert, Griffith, Obi L., Shah, Ronak H., Elamine, Leila, Ainscough, Benjamin J., Ebbesen, Saya H., Sgroi, Dennis, Griffith, Malachi, Won, Helen H., Isakoff, Steven, Lowe, Scott W., Derti, Adnan, Mino-Kenudson, Mari, Berger, Michael F.

2015

Overview

A study of genome evolution in a metastatic breast cancer bearing an activating PIK3CA mutation, following treatment with the PI(3)Kα inhibitor BYL719, shows that all metastatic lesions, when compared to the pre-treatment tumour, had lost a copy of PTEN; parallel genetic evolution of separate sites with different PTEN genomic alterations had led to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition. Anticancer resistance due to PTEN loss The emergence and expansion of resistant clonal subpopulations is a major challenge facing the field of targeted therapeutics. Here, the authors study genome evolution in a metastatic breast cancer bearing an activating PIK3CA mutation, following treatment with the phosphatidylinositol-4,5-bisphosphate 3-kinase alpha subunit (PI(3)Kα) selective-inhibitor BYL719. Fourteen metastatic sites were sequenced to reveal that all metastatic lesions, when compared to the pre-treatment tumour, had lost a copy of the gene for the tumour suppressor phosphatase PTEN . Resistance to BYL719 was associated with additional and different PTEN genetic alterations, resulting in loss of PTEN expression. Based on these observations and additional functional characterization, the authors conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition. 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 1 , 2 . 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.

• Publisher: Nature Publishing Group UK
• Subject: 13/106 / 13/109 / 13/44 / 13/51 / 13/95 / 45/22 / 45/23 / 64/60 / 692/308/575 / 82/1 / Alleles / Animals / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Class I Phosphatidylinositol 3-Kinases / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Female / Humanities and Social Sciences / Humans / letter / Loss of Heterozygosity - drug effects / Loss of Heterozygosity - genetics / Mice / Mice, Nude / multidisciplinary / Phosphatidylinositol 3-Kinases - antagonists & inhibitors / PTEN Phosphohydrolase - deficiency / PTEN Phosphohydrolase - genetics / PTEN Phosphohydrolase - metabolism / Science / Thiazoles - pharmacology / Thiazoles - therapeutic use / Xenograft Model Antitumor Assays