Trends in Pharmacological Sciences
Feature ReviewTargeted Therapies for Triple-Negative Breast Cancer: Combating a Stubborn Disease
Section snippets
Breast Cancer: Mixed Entities
With an estimated 1.7 million newly diagnosed cases in 2012 alone, breast cancer is the leading cause of cancer-related deaths among women globally [1]. Since the 2008 cancer census [2] a 20% increase in cancer incidence and a 14% increase in mortality have been recorded, indicating a sharp rise in breast cancer cases in recent years. Breast cancer prognosis and classification have historically relied on both analysis of tumor morphology and the expression of three (marker) proteins: the
Current Available Treatments for TNBC
Treatment for TNBC presents a major clinical challenge owing to an absence of causally proven high-frequency oncogenic drivers to target the vast disease heterogeneity 20, 41. Chemotherapy is the mainstay of treatment and generally involves administering anthracyclines, taxanes, and/or platinum compounds to disrupt cancer cell functions. Because a majority of TNBC patients do not achieve a pCR after chemotherapy, the nature of chemotherapy and whether chemotherapy choices should be different
Molecular Landscape of TNBC
Gene expression profiling has shown that approximately 70% of all TNBC tumors are basal-like [45] (recently reviewed in [46]); however, a significant number of basal-like tumors do express ER/PR or HER2 and at least one other basal molecular marker, mainly cytokeratins 5 and 6 (CK5/6), CK14, CK17, caveolin 1/2, and EGF receptor (EGFR). Therefore, TNBCs indeed represent a distinct histopathological subtype, which can be found represented in a variety of mRNA expression-based subtypes (Figure 1).
Exploiting BRCA Status for Targeted Therapy in TNBC Using Poly-ADP Ribose Polymerase Inhibitors (PARPi)
PARP inhibition has recently gained much attention as a promising target for treatment of cancers with BRCA1 mutation via synthetic lethality, in which simultaneous loss of two genes results in cell death but deletion of either individually does not impact on cell viability. BRCA1 is rarely mutated in sporadic TNBCs; however, a proportion of TNBC patients exhibit a BRCA1 mutation carrier-like phenotype where BRCA1 is inactivated by other means 52, 53, 54, 55, 56. Two seminal reports showed that
Refined Expression Signatures Suggest Novel Molecular Targets in TNBC
Omics-based profiling of TNBC patients and large-scale gene silencing using small interfering RNAs (siRNAs) and/or small hairpin RNAs (shRNAs) in cell line models of breast cancer have identified a handful of potentially druggable targets which have been tested both in cell lines and preclinical models (reviewed in [43]). For example, through unsupervised clustering of gene expression data from ER-negative breast tumors, Speers et al. [71] identified four distinct clusters of kinases: cell
Proteomics-Based Breast Cancer Classifiers and Novel Therapeutic Target Identification in TNBC
Emerging proteomics-based approaches have also been employed for the identification of new therapeutic targets in TNBCs. Reverse-phase protein array (RPPA) is being adopted in several recent studies to determine functional changes in protein expression between breast cancer subtypes 79, 80, 81. Using unsupervised clustering, Gonzalez-Angulo et al. [82] identified six major subgroups of breast cancer with significantly different recurrence-free (RFS) and OS outcomes. Using an overlapping but not
RTKs and Non-RTK Signaling Targets in TNBC
Several studies have also identified common signaling molecules in particular RTKs that are often elevated across cancers that could be actionable targets in TNBCs (Figure 2). RTKs are essential components of signal transduction pathways, and play vital roles in both autocrine and paracrine cell-to-cell communications. RTKs are involved in cell proliferation and differentiation, regulation of cell growth and metabolism, as well as promotion of cell survival and apoptosis (reviewed in 88, 89).
Inhibition of MAPK
The MAPK pathway represents a node in RTKs and other signaling networks, and lies subordinate to RAS and RAF activity in several cancers (reviewed in 128, 129). Aberrant activity of MAPK has been implicated in the development and progression of TNBCs (reviewed in [130]). The observed overexpression of this pathway in TNBC tumor cells may contribute to malignant transformation characterized by uncontrolled cell proliferation and resistance to apoptosis 131, 132, 133. Recent studies from TCGA
Other Promising Therapeutic Targets That Control the Cell Cycle and DNA Damage Response in TNBC
Targeting DNA damage-induced cell cycle arrest has become a major focus of chemotherapeutic research, and several pharmaceutical companies are exploring inhibitors of DNA damage checkpoint kinases including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and rad3-related protein (ATR), and checkpoint kinase 1/2 (CHK1/2). Interfering with cell cycle control has the potential to cause ‘inappropriate’ cell cycle progression, resulting in the accumulation of DNA damage, triggering cancer
Lymphocytic Infiltrates as a Predictive and Prognostic Marker for TNBC
Tumor-infiltrating lymphocytes (TILs) have gained much attention in recent years not only as a prognostic biomarker but also as predictive factors to determine the efficacy of conventional chemotherapies 186, 187. Gene expression profiling and immunohistochemistry (IHC) staining suggested that increased TILs are associated with better prognosis 188, 189, 190. This correlation has been also confirmed in meta-analysis of ER− tumors [191] and TNBC [192]. Whether better prognosis is directly linked
Acquisition Of Resistance to Targeted Therapies, and Strategies for Combination Therapy
Resistance may be classified as de novo or acquired, with some similar molecular mechanisms underlying both processes. In de novo resistance, a drug with proven efficacy in preclinical studies fails to elicit any detectable response upon initial treatment [225]. By contrast, acquired resistance occurs when tumor cells that were initially sensitive to the inhibitor stop responding, despite continued administration of the drug. In the case of RTK pathway inhibitors, evidence from in vitro and in
Concluding Remarks
Although TNBCs account for a relatively small percentage of diagnosed breast cancer cases, they cause a disproportionate number of deaths among patients. Large-scale genomic and proteomics studies have identified at least four molecularly-distinct subtypes within TNBCs, and these have enabled identification of putative targets specific to each subtype, supported by encouraging preclinical trials with new therapies. It is crucial to select the right set of patients for these clinical trials to
Acknowledgments
The authors thank Drs Jessie Jeffery and Amanda Bain from the Signal Transduction Laboratory, QIMR–Berghofer for critical reading of the manuscript and making valuable suggestions. We also thank the anonymous reviewer who edited this article thoroughly. Our laboratory is supported by grants from the Cancer Council Queensland (CCQ) project grant to M.K. (ID1087363) and the National Health and Medical Research Council (NHMRC) program grant to K.K.K. (ID1017028). K.K.K. is a NHMRC Senior Principal
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These authors contributed equally.