Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer

Abstract

Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.

Keywords: Breast cancer; Clinical trials; Immune-checkpoint Inhibitors; Immunotherapy; Targeted therapies.

Fig. 1

Crosstalk between PRLR and EGFR/HER2 signaling to promote breast cancer progression. PRL endorses PRLR activation, which recruits downstream pathways, such as JAK/STAT, MAPK/ERK, PI3K/AKT/mTOR, NEK3/VAV2/RhoA and TEC/VAV1/RAC1 involved in growth, survival, and migration of breast cancer. EGF/EGFR signaling somewhat overlaps with PRLR signaling to result in the activation of similar downstream events. PRLR/HER2 crosstalk endorses ER phosphorylation and promotes its attachment to the PRLR regulator and promotes PRLR transcription. EGF/EGFR can also trigger PRLR transcription in MAPK/PI3K-dependent manner. In addition, PRL/PRLR activation recruits HRE2 via JAK2 resulting an activation of FAC signaling that promotes cell adherence and induces metastasis. Arrows represent downstream events. AKT, Ak strain transforming; EGF, Epidermal growth factor; EGFR, Epidermal growth factor receptor; ER, Estrogen receptor; ERK, Extracellular signal-regulated kinase; GRB2, Growth factor receptor-bound protein 2; HER2, Human epidermal growth factor-2; JAK, Janus kinase, MAPK, Mitogen-activated protein kinase; mTOR, Mammalian target of rapamycin; NEK3, NIMA-related kinase 3; P, Phosphate; PI3K, Phosphoinositide 3-kinase; PRL, Prolactin; PRLR: Prolactin receptor; RhoA, Ras homolog family member A; STAT, Signal transducer and activator of transcription; TEK, TEK receptor tyrosine kinase; VAV, Vav guanine nucleotide exchange factor 1

Fig. 2

The mechanistic insight of CDK4/6 inhibitors in the management of breast cancer. CDK4/6 activation leads to Rb activation via phosphorylation. Activated Rb enables cell cycle progression by turning on E2F transcription. In addition, CDK4 and CDK6 endorse the stabilization and activation of FOXM1 via phosphorylation, which in turn promotes the upregulation of the G1/S phase genes and the avoidance of cell senescence. CDK4/6 inhibitors, such as palbociclib, ribociclib, or abemaciclib arrest the cell cycle by suppressing CDK4/6 downstream signaling event and arrest. Grey arrows represent downstream events and red lines represent inhibition. CDK, Cyclin-dependent kinase; FOXM1, Forkhead box protein M1; Rb: Retinoblastoma-associated protein

Fig. 3

AKT signaling pathway in breast cancer development and progression. It is a major intracellular pathway which leads to cell survival and cell proliferation. Activation of PI3K catalyzes the phosphorylation of PIP2 to PIP3, which further endorses PDK1 activation. Phosphorylation of FOXO1 by AKT inhibits its transcriptional activities resulting in cell growth, proliferation and survival. In addition, AKT inhibits TSC1/2 resulting in an activation of mTOR which simultaneously suppress autophagy and apoptosis and triggers proliferation. Gray arrows represent downstream events, gray lines represent inhibition, green up arrowheads represent activation/upregulation, and red down arrowheads represent suppression/downregulation. AKT, Ak strain transforming; Bad, Bcl-2-associated death promoter; FOXO, Forkhead box transcription factors; GPCR, G protein-coupled receptor; mTOR, Mammalian target of rapamycin; NO, Nitric oxide; PDK1, Phosphoinositide-dependent kinase-1; PI3K, Phosphoinositide 3-kinase; PIP2, Phosphoinositol 4, 5-biphosphate; PIP3, Phosphoinositol 3, 4, 5-triphosphate; PTEN, Phosphatase and tensin homolog is a phosphatase; TSC, Tuberous sclerosis complex

Fig. 4

FGFR signaling pathway in breast cancer as a potential therapeutic target. Attachment of FGFs to FGFRs causes their dimerization, which encourages TGFR1 activation through kinase domain activation loop with activation of FRS2, PLCγ and downstream transduction pathways, such as PI3K/AKT/mTOR, PKC, RAS/MAPK pathways, which potentiate proliferation, differentiation, migration, angiogenesis, and survival process. Arrows represent downstream events and the line represents inhibition. AKT, Ak strain transforming; ERK, Extracellular signal-regulated kinase; FGF, Fibroblast growth factor; FGFR, Fibroblast growth factor receptor; FRS2, Fibroblast growth factor receptor substrate 2; GRB2, Growth factor receptor-bound protein 2; JAK, Janus kinase; MEK, Mitogen-activated protein kinase kinase; mTOR, Mammalian target of rapamycin; PI3K, Phosphoinositide 3-kinase; PKC, Protein kinase C; RAF, Rapidly accelerated fibrosarcoma; RAS, Rat sarcoma; SOS, Son of sevenless; STAT, signal transducer and activator of transcription

Fig. 5

Immune escape mechanism of breast cancer cells and therapeutic role of immune checkpoint blockers in breast cancer treatment. When cytotoxic T-cells in the tumor microenvironment cannot be activated by immunological checkpoints or by the suppressive effect of Tregs, cancer cells are able to withstand the immune assault, survive, and proliferate. CTLA-4 is able to endorse Treg activity leading to an immunosuppressive effect. CTLA-4 binds to B7 (CD80 and CD86) expressed on APCs, such as DCs and inhibits T-cell-mediated immune response. In addition, the binding of CD28 with B7 on APCs suppresses T-cell activity. PD-1/PD-L1 system plays an important role later on and serves to abstract T-cell activity. When PD-1 binds to PD-L1, cytotoxic T-cells become anergic, which further encourages inhibitory signals. APC, Antigen presenting cell; CTLA-4, Cytotoxic T-lymphocytic antigen-4; DC, Dendritic cell; MHC, Major histocompatibility complex; PD-1, Programmed cell death-1; PD-L1. Programmed cell death-1 ligand; TCR: T-cell receptor; Treg, Regulatory T-cell