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


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 clones1,2. 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.

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Figure 1: Clinical response of index patient treated with BYL719.
Figure 2: Loss of PTEN upon BYL719 resistance.
Figure 3: Loss of PTEN by different genetic alterations.
Figure 4: Loss of PTEN expression and sensitivity to PI(3)Kα and PI(3)Kβ blockade.

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Data deposits

DNA sequences have been deposited in the European Genome-phenome Archive with accession number EGAS00001000991.


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We thank members of the MSKCC Diagnostic Molecular Pathology Laboratory and the MSK Maria-Josée and Henry Kravis Center for Molecular Oncology for assistance with sequencing. We thank M. Asher and U. Bhanot from the MSKCC Pathology Core for assistance with tissue staining. This work was funded by a “Stand Up to Cancer” Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209), the Breast Cancer Research Foundation, the Geoffrey Beene Cancer Research Center, the Starr Cancer Consortium and an MMHCC grant (CA105388). D.J. is also funded by a National Institutes of Health Training Grant (T32 CA-71345-15) and by philanthropic support from Stephen and Kathleen Chubb.

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Authors and Affiliations



D.J., P.C., M.F.B., J.B. and M.S. conceived the project, designed and analysed the experiments, and wrote the manuscript. M.G., O.L.G., B.J.A., A.R. and E.R.M. performed and analysed the WGS and WES data. T.H., M.M.-K., D.S., S.I., A.T., L.E., C.Q., M.P., A.D., R.B. and A.H. collected and analysed patients’ samples. P.C., H.E., S.H.E. and S.W.L. performed and supervised the laboratory experiments. H.H.W., G.I., R.H.S., D.B.S. and M.F.B. performed and supervised the IMPACT sequencing and analysis.

Corresponding authors

Correspondence to Michael F. Berger, José Baselga or Maurizio Scaltriti.

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Competing interests

C.Q., M.P., A.D. and A.H. are Novartis employees. D.J., D.B.S. and J.B. consult for Novartis.

Extended data figures and tables

Extended Data Figure 1 CT scan of index patient.

CT scan showing a liver lesion (baseline) experiencing a partial response after 8 cycles (cycle 8) of BYL719.

Extended Data Figure 2 Gene copy number variation in both primary tumour and lung metastasis.

Extended Data Figure 3 Representative exon-level copy number profiles for genes on chromosome 10 in all 14 metastases collected from the index patient.

Exons in PTEN are shown in red.

Extended Data Figure 4 Loss-of-function mutations in PTEN detected by IMPACT in metastases M06 and M10.

Mutations were visualized by the Integrative Genomics Viewer (IGV).

Extended Data Figure 5 PTEN immunostaining of the 14 metastases collected during the autopsy.

Haematoxylin and eosin (H&E) and PTEN expression detected by IHC in 14 metastases collected during the autopsy of the index patient. PTEN staining in PTEN negative samples is only present in stromal cells.

Extended Data Figure 6 PTEN immunostaining in patients treated with BYL719.

PTEN expression detected by IHC in paired samples from six additional patients treated with BYL719. Specimens before starting BYL719 therapy (baseline) and at time of disease progression (post-treatment) are compared.

Extended Data Figure 7 Inducible loss of PTEN and sensitivity to BYL719 and BKM120.

a. Cell viability assay in MCF7 cells with inducible PTEN knockdown treated with increasing concentrations of either BYL719 or BKM120. Error bars, s.e.m. b, Cell viability assay in MDA-MB-453 (MDA453) cells with constitutive PTEN knockdown treated with increasing concentrations of either BYL719 or BKM120. Error bars, s.e.m. c, Quantification of pAKT (S473) and pS6 (S240/4) from Fig. 4d. Student’s t-test was used and P values are indicated. d, Western blot from the PDXs treated as indicated.

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Extended Data Figure 8 Constitutive loss of PTEN and sensitivity to BYL719 and AZD6482.

a, Cell viability assay in T47D cells with inducible PTEN knockdown (no. 2) treated with increasing concentrations of either BYL719 or AZD6482 in the presence of doxycycline 1 μg ml−1. Error bars, s.e.m. b, Quantification of pAKT (S473) and pS6 (S240/4) from Fig. 4g. Student’s t-test was used and P values are indicated. Error bars, s.e.m. c, Western blot from the PDXs treated as indicated.

Extended Data Table 1 Samples analysed from the index patient

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Juric, D., Castel, P., Griffith, M. et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature 518, 240–244 (2015).

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