Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC

Abstract

Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

Keywords: biomarkers; breast cancer; chemoresistance; emerging therapies; triple-negative.

Figure 1

EGFR, IGF1-R, and PI3K-Akt-mTOR (PAM) pathway. Potential mechanisms of chemotherapy resistance (ctr) in TNBC. PI3K activation produces PIP3 from PIP2 substrate; Akt activation inhibits TSC, which acts as a GTPase activating protein for RHEB; mTORC1 induces hypoxia and angiogenesis via modulation of HIF-1; mTORC2 promotes apoptosis evasion/inhibition through NFkB, FKHR, and BAD; PTEN and TSC are significant tumor suppressors. IGF1: insulin growth factor 1; IGF1-R: insulin growth factor 1 receptor; CSC: cancer stem cell; NACT: neoadjuvant chemotherapy; EGFR: epidermal growth factor receptor; RTKs: receptors with protein tyrosine kinase activity; PIP2: phosphatidylinositol-4,5 biphosphate; PIP3: phosphatidylinositol-3,4,5 triphosphate; PH: protein with pleckstrin homology; Akt: protein kinase B; GTPase: guanosine triphosphatase; HIF-1: hypoxia inducible factor 1; IRS: insulin receptor substrate; mTORC1/2: mammalian target of rapamycin complex 1/2; PI3K: phosphatidylinositol 3 kinase; PTEN: phosphatase and tensin homolog deleted on chromosome 10; TSC: tuberous sclerosis; RHEB: RAS homolog enriched in brain (GTP-binding protein); FKHR: forkhead family transcriptor factors; ABC: ATP binding cassette; ABCG2: ATP binding cassette superfamily G member 2; NFkB: nuclear factor kappa-high chain enhancer of activated B cells; BAD: Bcl-2 associated death promoter. ↑ increase; ↓ decrease. Also see text.

Figure 2

Wnt-beta-catenin pathway. Potential mechanisms of chemotherapy resistance (ctr) in TNBC. FZD-8: Frizzled-8; NEK2B: NIMA related kinase 2; CSCs: cancer stem cells; CT: chemotherapy; TCF: T cell factor; LEF: lymphocyte enhancer factor; r.t.cs: residual tumor cells; NACT: neoadjuvant chemotherapy. ↑ increase; ↓ decrease. Also see text.

Figure 3

NFkB and JAK/STAT pathways. Potential mechanisms of chemotherapy resistance (ctr) in TNBC. NFkB is upregulated by hypoxia and activated through LPA-LPAR-EZH2-NFkB signaling cascade which results in autocrine production of IL-6 and IL-8. Extracellular IL-6, IL-8 ligand permits transphosphorylation of JAKs that successively phosphorylate STAT monomers. Activated STAT3 enters nucleus, where it governs transcription of many target genes; activated STAT3 also induces upregulation of ABCC2 and ABCC6, and therefore IL-6 and IL-8 by multiple pathways induce tumor growth, resistance to apoptosis, and chemotherapy resistance. LPA: lysophosphatidic acid; LPAR: LPA receptor; EZH2: enhancer of zeste homolog 2 (a gene component of polycomb repressive complex (PRC2) and epigenetic regulator); TME: tumor microenvironment; IL: interleukin; NFkB: nuclear factor kappa-high chain enhancer of activated B cells; STAT: signal transducer and activator of transcription; Src: Src family kinase; p38: p38 mytogen-activated protein kinase; PI3K: phosphatidylinositol 3 kinase. ↑ increase. Also see text.