PIK 3 CA and PIK 3 CB Inhibition Produce Synthetic Lethality when Combined with Estrogen Deprivation in Estrogen Receptor – Positive Breast Cancer

Several phosphoinositide 3-kinase (PI3K) catalytic subunit inhibitors are currently in clinical trial. We therefore sought to examine relationships between pharmacologic inhibition and somatic mutations in PI3K catalytic subunits in estrogen receptor (ER)–positive breast cancer, in which these mutations are particularly common. RNA interference (RNAi) was used to determine the effect of selective inhibition of PI3K catalytic subunits, p110A and p110B, in ER breast cancer cells harboring either mutation (PIK3CA) or gene amplification (PIK3CB). p110A RNAi inhibited growth and promoted apoptosis in all tested ER breast cancer cells under estrogen deprived-conditions, whereas p110B RNAi only affected cells harboring PIK3CB amplification. Moreover, dual p110A/p110B inhibition potentiated these effects. In addition, treatment with the clinical-grade PI3K catalytic subunit inhibitor BEZ235 also promoted apoptosis in ER breast cancer cells. Importantly, estradiol suppressed apoptosis induced by both gene knockdowns and BEZ235 treatment. Our results suggest that PI3K inhibitors should target both p110A and p110B catalytic subunits, whether wild-type or mutant, and be combined with endocrine therapy for maximal efficacy when treating ER breast cancer. [Cancer Res 2009;69(9):OF1–8]

[1]  J. Olson,et al.  Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial. , 2009, Journal of the American College of Surgeons.

[2]  A. Nobel,et al.  Supervised risk predictor of breast cancer based on intrinsic subtypes. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Jingqin Luo,et al.  Outcome Prediction for Estrogen Receptor–Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics , 2008, Journal of the National Cancer Institute.

[4]  P. Musiani,et al.  Phosphoinositide 3-Kinase p110β Activity: Key Role in Metabolism and Mammary Gland Cancer but Not Development , 2008, Science Signaling.

[5]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[6]  M. Loda,et al.  Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis , 2008, Nature.

[7]  S. H. Lee,et al.  Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias , 2008, British Journal of Cancer.

[8]  Bernd Giese,et al.  Targeting phosphoinositide 3-kinase: moving towards therapy. , 2008, Biochimica et biophysica acta.

[9]  O. Lingjaerde,et al.  ESR1 gene amplification in breast cancer: a common phenomenon? , 2008, Nature Genetics.

[10]  A. Marchetti,et al.  Different Prognostic Roles of Mutations in the Helical and Kinase Domains of the PIK3CA Gene in Breast Carcinomas , 2007, Clinical Cancer Research.

[11]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[12]  L. Skoog,et al.  PIK3CA Mutations and PTEN Loss Correlate with Similar Prognostic Factors and Are Not Mutually Exclusive in Breast Cancer , 2007, Clinical Cancer Research.

[13]  S. Lee,et al.  Targeted RNA interference of phosphatidylinositol 3‐kinase p110‐β induces apoptosis and proliferation arrest in endometrial carcinoma cells , 2007, The Journal of pathology.

[14]  M. Monden,et al.  Clinicopathologic Analysis of Breast Cancers with PIK3CA Mutations in Japanese Women , 2007, Clinical Cancer Research.

[15]  Hailing Cheng,et al.  The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation , 2006, Proceedings of the National Academy of Sciences.

[16]  Hao Jiang,et al.  Downregulation of PIK3CB by siRNA Suppresses Malignant Glioma Cell Growth In Vitro and In Vivo , 2006, Technology in cancer research & treatment.

[17]  Robbie Loewith,et al.  A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling , 2006, Cell.

[18]  K. Okkenhaug,et al.  Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation , 2006, Nature.

[19]  B. Giovanni.  Proliferation and apoptosis as markers of benefit in neoadjuvant endocrine therapy of breast cancer , 2006 .

[20]  N. Ahmad,et al.  RNA interference-mediated depletion of phosphoinositide 3-kinase activates forkhead box class O transcription factors and induces cell cycle arrest and apoptosis in breast carcinoma cells. , 2006, Cancer research.

[21]  B. Iacopetta,et al.  PIK3CA mutations in breast cancer are associated with poor outcome , 2006, Breast Cancer Research and Treatment.

[22]  M. Loda,et al.  The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells , 2005 .

[23]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[24]  J. Engelman,et al.  Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. , 2005, Cancer research.

[25]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[26]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[27]  R. Chibbar,et al.  Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen , 2005, Modern Pathology.

[28]  M. Dowsett,et al.  Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[30]  M. J. van de Vijver,et al.  Overexpression of P70 S6 kinase protein is associated with increased risk of locoregional recurrence in node-negative premenopausal early breast cancer patients , 2004, British Journal of Cancer.

[31]  B. Vanhaesebroeck,et al.  Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta. , 2003, Cancer research.

[32]  A. Klippel,et al.  Functional studies of the PI(3)-kinase signalling pathway employing synthetic and expressed siRNA. , 2003, Nucleic acids research.

[33]  J. Kononen,et al.  Multiple genes at 17q23 undergo amplification and overexpression in breast cancer. , 2000, Cancer research.

[34]  K. Ley,et al.  phosphatidylinositol-3-OH kinase , 2000 .

[35]  M. Dowsett,et al.  Time‐related effects of estrogen withdrawal on proliferation‐ and cell death‐related events in MCF‐7 xenografts , 1999, International journal of cancer.

[36]  M. Westerfield,et al.  Characterization of paired tumor and non‐tumor cell lines established from patients with breast cancer , 1998, International journal of cancer.

[37]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[38]  P. Bontempo,et al.  Tyrosine kinase/p21ras/MAP‐kinase pathway activation by estradiol‐receptor complex in MCF‐7 cells. , 1996, The EMBO journal.

[39]  A. Wärri,et al.  Apoptosis in toremifene-induced growth inhibition of human breast cancer cells in vivo and in vitro. , 1993, Journal of the National Cancer Institute.

[40]  N. Davidson,et al.  Programmed cell death during regression of the MCF-7 human breast cancer following estrogen ablation. , 1991, Cancer research.