Targeting of estrogen receptor is commonly used as a first-line treatment for hormone-positive breast cancer patients, and is considered as a keystone of systemic cancer therapy. Likewise, HER2-targeted therapy significantly improved the survival of HER2-positive breast cancer patients, indicating that targeted therapy is a powerful therapeutic strategy for breast cancer. However, for triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, there are no clinically approved targeted therapies, and thus, an urgent need to identify potent, highly effective therapeutic targets. In this mini-review, we describe general strategies to inhibit tumor growth by targeted therapies and briefly discuss emerging resistance mechanisms. Particularly, we focus on therapeutic targets for TNBC and discuss combination therapies targeting the epidermal growth factor receptor (EGFR) and associated resistance mechanisms.

Introduction

Triple-negative breast cancer (TNBC) is a highly aggressive heterogenous disease, defined by the absence of estrogen and progesterone receptors and of HER2 amplification. It is characterized by high mitotic indices, high rates of metastasis and poor prognosis [1,2]. The disease is prevalent among premenopausal and young women and accounts for 15–20% of all breast carcinoma [3].

Transcriptomic profiling analysis using different classification methods defined 4–7 distinct molecular subtypes displaying different molecular properties, histopathology, clinical features and survival outcomes [4,5]. In 2012, Lehman et al. [6], defined at least six different subtypes including two basal-like (BL1 and BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR), while on 2016, the same author refined four molecular subtypes, including LAR, BL1, BL2 and mesenchymal [7]. Other methods identified four subtypes of either LAR and BL, and classified the non-basal into claudin-low and claudin-high [8], or of LAR and mesenchymal and classified the BL into BL/immune-suppressed (BLIS), and BL/immune activated (BLIA) [4]. Basal-like TNBC, which accounts for 50–75% of all TNBC, express several characteristic biomarkers, including specific cytokeratins (CK5, CK6, CK14, CK17), epidermal growth factor receptor (EGFR), SMA (smooth muscle actin), P-cadherin, p63 and c-kit, and are characterized by high proliferation rate concomitant with high expression of cell cycle-related genes [9].

In addition to the transcriptomic diversity, genomic analysis suggests that TNBCs display a unique landscape of genetic alterations and high genomic instability [10]. Genomic aberrations were identified in several oncogenes and tumor suppressors; most frequent somatic mutations were observed in TP53 (∼85%). Mutations in PIK3CA (∼10%), USH2A (usher syndrome 2A) (∼9%), MYO3A (myosin IIIA) (∼9%), PTEN and RB1 genes (∼8%) were also identified, as well as copy numbers alterations in RB1 (5%), amplification of MYC (26%) or EGFR (5%) [11].

This remarkable diversity in genomic and transcriptomic landscapes of TNBC emphasizes the urgent need to develop different therapeutic regimens to each molecular subtype and individual patients. Currently, the standard care of tumor resection, cytotoxic chemotherapy and radiation is benefit for only 20–30% of TNBC patients, and is associated with high frequency of recurrence within the 1–3 years after diagnosis [12]. Importantly, a recent clinical trial indicates that TNBC patients with the high expression level of programmed death-ligand 1 (PD-L1) could be benefit from combination therapy of PDL1 blockade (Atezolizumab) and conventional chemotherapy [13]. Consequently, this combination was approved by the FDA (Food and Drug Administration) for a subset of TNBC patients [14]. These encouraging results further demonstrate the power of targeted therapy and highlights the requirement for precision therapy in TNBC.

Common strategies of targeted therapies rely on established concepts, which discriminate normal from cancer cells. For example, targeting of a specific oncogenic pathway due to ‘oncogene addiction’ of tumor cells or targeting of a non-oncogene due to a ‘non-oncogene addiction’. The targeting of synthetic lethal interactions is also a powerful approach and is briefly discussed in this mini-review along with emerging resistant mechanisms. Further information on TNBC therapies are summarized in several excellent recent review papers [3,15,16].

Targeted cancer therapy

A major challenge in cancer therapy is to selectively target cancer cells, exploiting their distinct malignant phenotype of uncontrolled cell growth and proliferation. As multiple genetic lesions in oncogenes or tumor suppressors are involved in cancer initiation and maintenance, targeting of these oncogenic pathways could be a very powerful strategy to inhibit tumor growth. Substantial preclinical and clinical studies suggest that many cancers are driven by specific oncogenic driver mutations, are dependent on a single oncogenic pathway and susceptible to inhibition of single oncogenes, a concept known as ‘oncogene addiction’ [17]. Possibly the best example of successful targeting therapy exploiting this concept is targeting of BCR-ABL1 fusion protein in chronic myeloid leukemia (CML) driven by chromosomal translocation between chromosome 9 and 22, known as the Philadelphia chromosome (Ph) [18]. Imatinib (Gleevec), a small molecule kinase inhibitor selective for BCR-ABL1 was approved by the FDA on 2001, and found to significantly increase the overall survival rate of CML patients by 10 years [19]. Another well-known example is Iressa (gefitinib), an EGFR kinase inhibitor, approved by the FDA on 2015 as a first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring specific mutations in EGFR [20].

In addition to oncogene targeting due to ‘oncogenic addiction’, many tumors are dependent on different cellular proteins that are not oncogenes and not involved in tumor initiation, but are absolutely required for tumor survival and/or growth in the presence of a specific perturbation. This phenomenon is called ‘non-oncogene addiction’ [21], and could be exploited for cancer therapy. For example, targeting the proteasome by the small molecule inhibitor bortezomib is effective in KRAS mutant tumors [22].

Another effective approach of targeted therapies relies on the concept of synthetic lethally between two or more genes where the loss of either of them alone has no effect on cell viability, while their combined loss induces lethal phenotype [23]. Synthetic lethality can occur not only between two genes, but also as a result of treatment with two different drugs, and could be either classical or essentiality-induced in which targeting of one gene induces the essentiality for the second one [24]. The power of synthetic lethality in cancer therapy is reflected by the remarkable sensitivity of BRCA1/2-positive mutant tumors to PARP (poly (ADP-ribose) polymerase) inhibitors. As BRCA1/2 are involved in DNA repair of double-strand breaks (DSB) by homologous recombination (HR), their inactivation results in impaired HR and increases the requirement of alternative DNA damage repair mechanisms such as non-homologous end-joining (alt-NHEJ) and base excision repair (BER) pathways, which require PARP1. Therefore, inhibition of PARP1 in these cells induces lethal death phenotype [25,26]. Currently, PARP inhibitors were approved by the FDA for the treatment of ovarian and breast cancers patients with BRCA mutations. Importantly, up to 15% of TNBC patients harbor germline mutations in the BRCA, particularly in BRCA1 [27], and two PARP inhibitors olaparib and talazoparib have been approved by the FDA for TNBC patients with BRCA mutations [28]. Nevertheless, resistance to PARP inhibitors remained a problem in clinic [29].

Therapy resistance

While a few examples of targeted therapies have been proven as highly effective anti-cancer drugs, numerous therapeutic targets induced robust initial clinical responses but eventually relapse due to intrinsic or acquired drug resistance (Figure 1) [17]. Intrinsic drug resistance commonly exists prior to drug administration, and the applied drug selectively eliminates sensitive cells, leaving the pre-existing resistant cells to grow and proliferate [30]. In contrast, acquired resistance occurs in response to drug exposure due to the acquisition of genetic or epigenetic events in a subset of cells that eventually lead to their survival, proliferation and expansion [31]. Acquired resistance due to the development of second mutations in the drugs targets has been reported for many targeted therapies. For example, gatekeeper mutations in the kinase domain of BCR-ABL (such as T315I) confer resistance to Imatinib in CML. Similarly, the T790M mutation in EGFR accounts for resistance (30–50%) to first- and second-generation tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib and afatinib) in NSCLC [32], and acquired mutations in MEK are associated with resistance to MEK1/2 inhibitors. The C121S mutation in MAP2K1 is associated with resistance to BRAFV600E inhibition by vemurafinib [17], and reactivation mutations in BRAC1/2 can restore HR and circumvent PARP inhibition [29].

Resistance to targeted therapy.

Figure 1.
Resistance to targeted therapy.

Resistance might emerge through a selection mode which eliminates the majority of cells but leaves pre-existing resistant cells that eventually proliferate and expand. In the adaptation mode, a subset of cells acquires genetic or epigenetic alterations leading to survival and expansion of the genomic-altered cells. Adaptation could also induce drug resistance via a non-genetic signaling rewiring mode by perturbating signaling cross-talk and feedback loops. Inhibition of MEK, for example, relieves the suppression of cMyc on RTKs, thereby enhancing transcription of certain RTKs including AXL, HER2/3, PDFGR. Another feedback loop involves AKT-mediated FOXO phosphorylation and the consequent suppression of a few RTKs (Insulin, IGF-1R, HER3) transcription. This suppression can be relieved by AKT inhibition, leading to RTKs transcription.

Figure 1.
Resistance to targeted therapy.

Resistance might emerge through a selection mode which eliminates the majority of cells but leaves pre-existing resistant cells that eventually proliferate and expand. In the adaptation mode, a subset of cells acquires genetic or epigenetic alterations leading to survival and expansion of the genomic-altered cells. Adaptation could also induce drug resistance via a non-genetic signaling rewiring mode by perturbating signaling cross-talk and feedback loops. Inhibition of MEK, for example, relieves the suppression of cMyc on RTKs, thereby enhancing transcription of certain RTKs including AXL, HER2/3, PDFGR. Another feedback loop involves AKT-mediated FOXO phosphorylation and the consequent suppression of a few RTKs (Insulin, IGF-1R, HER3) transcription. This suppression can be relieved by AKT inhibition, leading to RTKs transcription.

While this acquired drug resistance associates with genomic alterations, a non-genomic ‘adaptive resistance’ is frequently associated with tumor relapse and involved dynamic rewiring of signaling and/or transcriptional networks to circumvent drugs inhibition [33]. This kind of signaling rewiring adaptive resistance results from perturbation in pathways cross-talk and feedback regulatory loops that eventually bypass drug inhibition and rapidly induce resistance to targeted therapy [34]. Adaptive kinome reprogramming is frequently associated with resistance to kinase inhibitors and is commonly involved an up-regulation of different RTKs (receptor tyrosine kinases) expression. For example, inhibition of MEK1/2 in TNBC can be bypassed by increasing the expression of PDGFR-β and AXL. As ERK phosphorylates (at Ser62) and stabilizes cMYC, and cMYC suppresses RTK transcription, inhibition of MEK leads to rapid degradation of cMyc and consequently transcription of RTKs (Figure 1) [35]. Additional examples of RTKs-associated drug resistance are described below.

The different resistance mechanisms to targeted therapies (Figure 1) strongly indicates that monotherpeutic agents are not effective, and instead, combination therapies applying two or more drugs could increase treatment efficacy and/or prevent drug resistance [36]. Combination therapies for the different TNBC subtypes have been described in multiple preclinical settings, and combination therapies targeting EGFR are discussed in more details.

Therapeutic targets for TNBC

Unlike HER2- or hormone-positive breast cancer (ER/PR), TNBC has no prominent oncogenic driven mutations. Rather, most of the somatic mutations are found in tumor suppressor genes, such as TP53 (∼85%), RB1 (∼20%) and PTEN (35%), which currently are undruggable targets [11,15]. Oncogenic mutations are less prevalent, but were identified in PI3K (PI3KCA ∼10%), which together with the high frequency of AKT3 amplification (28%) and of PTEN loss/inactivation (35%) [37] suggest that targeting of the PI3K/AKT/mTOR pathway (activated in 60% of the patients) could be a promising therapeutic approach [38]. Indeed, multiple preclinical and clinical trials result in a significant outcome improvement, and suggest that combination therapies targeting the PI3K/AKT/mTOR pathway together with chemotherapy or other targeted therapy such as PARP inhibitor could be a promising approach [39]. Targeting the IL-6/JAK2/STAT3 pathway was also considered as a potent approach, possibly to eliminate cancer stem cell-like cells of basal-like breast cancer [40]. Additional promising targets controlling cell cycle and DNA damage response have been extensively examined in different settings. CHK1/2 (checkpoint kinase 1/2), for example, which is highly expressed in fast proliferative and genomic unstable tumors, such as TNBC, is required for cell-cycle arrest in response to DNA damage and thus influences DNA repair. Inhibition of CHK1/2, particularly in cancer with TP53 mutation, leads to accumulations of DNA damage and apoptotic cell death [41]. Similar effects were obtained with inhibition of WEE1, a G2 checkpoint protein, in TP53 mutant TNBC [42]. CDKs (cyclin-dependent kinases), in particular CDK1, CDK2, CDK4 and CDK6, were also considers as promising targets. Co-inhibition of CDK1/2 and MYC (amplify in ∼26% of TNBC) result in synthetic lethally [43], while inhibition of CDK4/6 was highly effective in RB-positive TNBC [44,45]. RB1-deficient TNBC cells are resistant to co-inhibition of CDK4/6 and CDK2, but are very sensitive to either CDC25 inhibitors, which synergized with WEE1 or PI3K inhibitors [46], or to Aurora A kinase inhibition, which showed synthetic lethal interaction with RB1 [47]. Combining of CDKs kinase inhibitors with other inhibitors such of PARP or the BET family of epigenetic readers, could also be a promising approach. Notably, although CDK1/2/4/6 are not mutated or overexpressed in TNBC, but were proposed as effective therapeutic targets in specific context exploiting the concept of non-oncogenic addiction. In addition, several RTKs including FGFR, VEGFR, PDFGR, IGFR1, AXL, MET and EGFR [48], have been proposed as therapeutic targets for different TNBC subsets. Below we focus on EGFR.

Targeting of EGFR in TNBC

EGFR is highly expressed in TNBC, particularly in the basal-like and mesenchymal stem-like subtypes [49,50]. Gene amplification has been observed in 6–21% of patients, dependent on the applied method, and overall overexpression was reported in 30–50% with a significant correlation with poor overall survival [51,52]. Activating mutations are rare in TNBC, but have been identified in ∼11.5% of Asian patients [53]. In light of the high expression level of EGFR and its strong effect on cell proliferation and motility, EGFR has been considered as an attractive therapeutic target for TNBC [54–56].

Several EGFR antagonists including small molecule kinase inhibitors (gefitinib, erlotinib) or monoclonal antibodies (cetuximab, panitumumab) have been approved for clinical use [56]. Nevertheless, using anti-EGFR as a monotherapy had marginal efficacy in clinical trials due to drug resistance [57,58]. Resistance to EGFR monotherapy is not restricted to TNBC and was reported for many other cancers. In many cases, EGFR-resistance was associated with overexpression of MET or its ligand HGF [59,60], and co-inhibition of EGFR and MET in TNBC had synergistic effects in vitro and inhibitory effects on tumor growth in animal models [61,62]. The RTK AXL, is also up-regulated in response to EGFR antagonists and is involved in resistance to EGFR-targeted therapy in the lung [63]. In TNBC, AXL is highly expressed in the mesenchymal subtype, is involved in EMT [64,65] and desensitizes tumor cells to EGFR inhibition [66].

Several studies suggest that inhibition of EGFR in TNBC results in the up-regulation of HER3, a member of the ErbB family, and that its downstream signaling compensates for EGFR inhibition through the loss of AKT signaling and AKT-mediated negative-feedback signaling [67]. Indeed, inhibition of AKT signaling by PI3K inhibitor (such as XL147) results in a compensatory increase in HER3 level and its phosphorylation [55,68]. As AKT suppresses FOXO-mediated transcription of HER3 and several other RTKs (Figure 1), inhibition of AKT relieves this negative feedback and increases HER3 expression [69]. It was, therefore, proposed that the concomitant blockade of EGFR, HER3, and the PI3K–AKT pathway could be beneficial for TNBC [67].

Another effective strategy to circumvent HER3-associated resistance to EGFR antagonist in basal-like TNBC is co-targeting of EGFR together with PYK2 [70], a non-receptor tyrosine kinase related to FAK (focal adhesion kinase) [71]. PYK2 is a downstream effector of EGFR [72] and high expression of both EGFR and PYK2 in TNBC correlates with overall reduced survival of basal-like breast cancer patients. Co-targeting of EGFR and PYK2 synergistically inhibited cell growth in vitro and tumor growth in the animal model. Importantly, PYK2 depletion or inhibition markedly reduced the steady-state level of HER3 in multiple TNBC cell lines and consequently bypassed resistance to EGFR antagonists. Mechanistic studies suggest that PYK2 inhibition facilitates the proteasomal degradation of HER3 and concomitantly increases the expression of NDRG1 (N-myc downstream regulated 1 gene), a stress response protein [73] implicated in multiple cellular processes, including multivesicular body formation and endosomal trafficking [74]. NDRG1 was localized to the endosomal compartment, partially colocalized with HER3 and enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2 that interacts with both NEDD4 and HER3 interfered with NEDD4–HER3 binding. Depletion or inhibition of PYK2 enhanced HER3 ubiquitination and its subsequent proteasomal degradation, suggesting that the PYK2–NDRG1–NEDD4 axis plays a key role in HER3 degradation, and that co-targeting of EGFR and PYK2 in basal-like TNBC not only inhibits tumor growth, but also circumvents HER3-associated resistance, and thus, could have a significant therapeutic impact.

Indeed, a systems-based approach that integrates mathematical network modeling with experimental data of EGFR signaling in basal-like TNBC predicted a synergy of EGFR and PYK2 co-inhibition. The combination eliminated negative network rewiring and reactivation of ERK and STAT3 caused by inhibition of either EGFR or PYK2 alone [75]. Furthermore, model-based stratification of TNBC patients identifies subgroups of patients that could benefit from this combination therapy, and suggested that PYK2 is significantly up-regulated in the synergistic patient group [75]. Collectively these results suggest that the application of computational systems modeling is a powerful approach to predict drug-induced network rewiring and synergistic drugs combinations [76,77]. It is worth mentioning that co-inhibition of EGFR and FAK signaling in TNBC through binding of Nephritis Antigen Like 1 (Tinagl1) to EGFR and integrin α5β1, αvβ1, suppressed TNBC progression and metastasis in preclinical models [78], implying that combination therapies targeting EGFR together with kinases of the PYK2/FAK family could be beneficial for subsets of TNBC patients.

Other reports suggested that a mixture of anti-EGFR antibodies including noncompetitive mAbs robustly induced lysosomal degradation of EGFR and inhibited the growth of TNBC in animals [79], thus offering an effective therapeutic strategy. Interestingly, a few recent clinical trials for TNBC patients employ anti-EGFR antibodies, either conjugated to the cytotoxic agent maytansinoid mertansine (DM1) (NCT03094169) or as doxorubicin-loaded anti-EGFR immunoliposomes, as first-line therapy in patients with advanced triple-negative, EGFR positive breast cancer (NCT02833766). Combining of EGFR inhibitors with chemotherapies, using erlotinib and doxorubicin, respectively [80], was also proposed as a promising therapeutic approach, and a current phase 2 clinical trial of cetuximab (Erbitux; EGFR binding FAB) and Ixabepilone (NCT01097642) is ongoing. Combining of lapatinib (EGFR/HER2 TKI, FDA approved on 2013; [81]) and PARP inhibitor ABT-888 (Veliparib) was also effective in preclinical models. This synthetic lethal combination impaired double-strand DNA breaks repair and consequently induced apoptotic cell death and attenuated tumor growth in xenografts animal model [82]. Importantly, a clinical trial for metastatic TNBC using combination of Veliparib and lapatinib is currently ongoing (NCT02158507). Previous clinical trials of lapatinib and Everolimus (mTOR inhibitor) (NCT01272141) or Erlotinib and Metformin (NCT01650506) have already been terminated without a significant outcome.

Overall, current ongoing clinical trials using either EGFR antagonists in combination therapy or anti-EGFR antibodies as a vehicle for drug targeting in TNBC, suggest that EGFR is a promising target for therapeutic intervention in combination therapy and/or for a specific subset of TNBC patients.

Perspectives

  • Importance of the field: Identification of highly potent targeted therapies and effective therapeutic strategies for different TNBC patients is an unmet challenging need, considering the intra- and intertumoral heterogeneity, intolerable side-effects, and drug resistance.

  • Current thinking: Targeted therapies applied as a single agent are not effective as drug resistance is rapidly emerged. Combining different drugs could be an effective approach to overcome drug resistance and to sustain drug efficacy over time, especially if the drug targets display synthetic lethal interactions.

  • Future directions: Therapeutic approaches combining targeted therapies with chemotherapy and/or immunotherapy, should be eventually designed for each TNBC patients based in their genomic profile, transcriptomic landscape, and immunogenic properties. Promising therapeutic strategies should be tested by clinically relevant experimental models.

Competing Interests

The author declares that there are no competing interests associated with this manuscript.

Funding

This work was supported by the Israel Science Foundation (ISF) grant no. 1530/17 and by the ISF-NSFC joint research program (grant no. 2526/16), by the MDACC-SINF grant and by a research grant from David E. Stone.

Author Contribution

S.L. wrote the manuscript and prepared the figure.

Acknowledgements

Sima Lev is the incumbent of the Joyce and Ben B. Eisenberg Chair of Molecular Biology and Cancer Research.

Abbreviations

     
  • BER

    base excision repair

  •  
  • CML

    chronic myeloid leukaemia

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • FDA

    Food and Drug Administration

  •  
  • HR

    homologous recombination

  •  
  • IM

    immunomodulatory

  •  
  • LAR

    luminal androgen receptor

  •  
  • MSL

    mesenchymal stem-like

  •  
  • NSCLC

    non-small cell lung cancer

  •  
  • RTKs

    receptor tyrosine kinases

  •  
  • TNBC

    triple-negative breast cancer

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