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      Efficacy of PI3K inhibitors in advanced breast cancer

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          Abstract

          The phosphoinositide 3 (PI3)-kinase/Akt signaling pathway has always been a focus of interest in breast cancer due to its role in cell growth, cell proliferation, cell migration and deregulated apoptosis. Its activation has been linked to endocrine resistance and worse prognosis in certain subgroups of breast cancer. In addition, deregulation of the PI3K/Akt pathway including PIK3CA activating mutation is frequently present in breast cancer. Multiple efforts have been carried out to target this pathway, initially with pan-PI3K inhibitors with some hint of activity but hampered by their limiting side-effects. A recent large randomized trial in patients with endocrine-resistant PIK3CA-mutant hormone receptor (HR)-positive tumors led to the approval of the first PI3K inhibitor, alpelisib, in combination with fulvestrant. The specificity of alpelisib against the p110α catalytic isoform provided additional efficacy and a better toxicity profile. In this review, we summarize the main research with PI3K inhibitors in breast cancer and we provide some insight of potential future combinations of this treatment in breast cancer patients.

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          PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

          J. Li, C. Yen, D Liaw … (1997)
          Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
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            An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

            Katherine Stemke-Hale, Ana Maria Gonzalez-Angulo, Ana Lluch … (2008)
            Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.
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              A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.

              John D Carpten, Andrew L Faber, Candice Horn … (2007)
              Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Oncol
                Journal ID (iso-abbrev): Ann. Oncol
                Journal ID (publisher-id): annonc
                Title: Annals of Oncology
                Publisher: Oxford University Press
                ISSN (Print): 0923-7534
                ISSN (Electronic): 1569-8041
                Publication date (Print): December 2019
                Publication date (Electronic): 20 December 2019
                Publication date PMC-release: 20 December 2019
                Volume: 30
                Issue: Suppl 10 , Phosphatidylinositol-3-kinase inhibitors in hormone receptor-positive breast cancer
                Pages: x12-x20
                Affiliations
                [1 ] Medical Oncology Department, Gustave Roussy Cancer Campus , Villejuif, France
                [2 ] IOB Institute of Oncology , Quiron, Madrid & Barcelona
                [3 ] Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona
                [4 ] Medica Scientia Innovation Research (MedSIR) , Valencia, Spain
                [5 ] Medica Scientia Innovation Research (MedSIR) , New York, USA
                [6 ] Medical Oncology Department, Centre Léon Bérard , Lyon
                [7 ] Inserm Unit U981, Gustave Roussy Cancer Campus , Villejuif
                [8 ] Université Paris Sud , Paris-Saclay, France
                Author notes
                Correspondence to: Dr Monica Arnedos, Department of Medical Oncology, Gustave Roussy Cancer Campus, 114 Rue Edouard Vaillant, Villejuif 94805, France. Tel: +33-1-42-11-43-71; E-mail: monica.arnedos@ 123456gustaveroussy.fr
                Author information
                http://orcid.org/0000-0001-5269-1251
                Article
                Publisher ID: mdz381
                DOI: 10.1093/annonc/mdz381
                PMC ID: 6923787
                PubMed ID: 31859349
                SO-VID: c69628bf-8b1f-4a21-aff9-4623878c3275
                Copyright © © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 9
                Funding
                Funded by: Novartis 10.13039/100004336
                Funded by: AstraZeneca 10.13039/100004325
                Categories
                Subject: Reviews

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pi3k inhibitors,breast cancer,targeted therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: pi3k inhibitors, breast cancer, targeted therapy

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