Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies.
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ABSTRACT:
SUBMITTER: Ocana A
PROVIDER: S-EPMC5400659 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
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Targeting oncogenic vulnerabilities in triple negative breast cancer: biological bases and ongoing clinical studies.
Ocana Alberto A Pandiella Atanasio A
Oncotarget 20170301 13
Triple negative breast cancer (TNBC) is still an incurable disease despite the great scientific effort performed during the last years. The huge heterogeneity of this disease has motivated the evaluation of a great number of therapies against different molecular alterations. In this article, we review the biological bases of this entity and how the known molecular evidence supports the current preclinical and clinical development of new therapies. Special attention will be given to ongoing clini ...[more]
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Project description:BackgroundAmong breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities.MethodsWe quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects.ResultsTNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases.ConclusionsSimilar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.
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Project description:Triple-negative breast cancer (TNBC) is currently the only major breast tumor subtype without effective targeted therapy and, as a consequence, in general has a poor outcome. To identify new therapeutic targets in TNBC, we performed a short hairpin RNA (shRNA) screen for protein kinases commonly amplified and overexpressed in breast cancer. Using this approach, we identified AKT3 as a gene preferentially required for the growth of TNBCs. Downregulation of Akt3 significantly inhibits the growth of TNBC lines in three-dimensional (3D) spheroid cultures and in mouse xenograft models, whereas loss of Akt1 or Akt2 have more modest effects. Akt3 silencing markedly upregulates the p27 cell-cycle inhibitor and this is critical for the ability of Akt3 to inhibit spheroid growth. In contrast with Akt1, Akt3 silencing results in only a minor enhancement of migration and does not promote invasion. Depletion of Akt3 in TNBC sensitizes cells to the pan-Akt inhibitor GSK690693. These results imply that Akt3 has a specific function in TNBCs; thus, its therapeutic targeting may provide a new treatment option for this tumor subtype.
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Project description:Triple-negative breast cancer (TNBC) is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer. TNBC accounts for approximately 10%-15% of all diagnosed breast cancer cases and represents a high unmet need in the field. Up to just a few years ago, chemotherapy was the only systemic treatment option for this subtype (1). To date, TNBC is considered a heterogeneous disease. One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases, in which Lehman et al. proposed six subtypes of TNBC as follows: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype, and a luminal androgen receptor (LAR) subtype (2). Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes (TILs) or stromal cells. According to this finding, the classification of TNBC has been revised into the following four subtypes: basal 1, basal 2, LAR, and mesenchymal subtypes (3). Over the last years, several new strategies have been investigated for the treatment of patients with TNBC. Among them, immunotherapy, antibody drug conjugates, new chemotherapy agents, and targeted therapy have been and are currently being developed. The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.
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