Shedding light on triple-negative breast cancer with Trop2-targeted antibody-drug conjugates

Abstract

Triple-negative breast cancer (TNBC) is well-known as the most aggressive subtype of breast cancer. Because TNBC does not express Her2, estrogen receptor, and progesterone receptors, there had been no effective U.S. Food and Drug Administration-approved targeted therapy for it until PARP inhibitors and two PD-1/PD-L1 monoclonal antibodies were approved for treatment of TNBC. Most recently, an antibody-drug conjugate (ADC), called sacituzumab govitecan (SG), was approved for the treatment of TNBC patients previously received chemotherapy with advanced disease. SG consists of an anti-trophoblast cell-surface antigen 2 (Trop2) antibody conjugated with a topoisomerase I inhibitor, SN-38, which is diffused out of the targeted Trop2 positive cancer cells and induces the bystander killing effect on surrounding cells regardless of their Trop2 expression status. In the Phase III clinical trial, TNBC patients treated with SG showed significantly longer progression-free and overall survival compared to those who were received chemotherapy. In the present review, we summarized the cellular function and signaling of Trop2, the mechanism of action of SG, and the clinical trials of SG that led to its quick approval for TNBC. In addition, we introduced the current ongoing clinical trials of SG as well as another Trop2 ADC, which has potential to overcome some disadvantages of SG.

Keywords: SN-38; Triple-negative breast cancer; Trop2; antibody-drug conjugates; sacituzumab govitecan.

Figure 1

The Trop2-mediated signaling pathways. Trop2 activation is either dependent or independent on growth factors. Trop2 then increases internal Ca2⁺ level and enhances protein kinase C (PKC) signaling. On the other hand, Trop2 phosphorylation recruits RACK1 scaffold protein by which Trop2 interacts with other signaling pathways such as PI3K/Akt and MAPK pathways as well as FAK signaling. Furthermore, separation of transmembrane and intracellular parts of Trop2 by γ-secretase and ADAM-17, and its migration into nuclease interacts with other genes related to cancer progression. Overall, Trop2 can enhance cell proliferation, cell growth, and cell migration through several mechanisms. AP1: Activator protein 1; DAG: Diacylglycerol; ECD: Extracellular domain; ERK1/2: Extracellular signal-regulated kinase 1/2; FAK: Focal adhesion kinase; IP3: Inositol trisphosphate; ICD: Intracellular domain; MAPK: Mitogen-activated protein kinase; PARP1: poly (ADP-ribose) polymerase-1; PIP2: Phosphatidylinositol 4,5-bisphosphate; RACK1: receptor for activated C kinase 1; ADAM17: A disintegrin and metalloprotease 17.

Figure 2

Differential Trop2 gene (TACSTD2) expression analysis in different tumor, normal and metastatic tissues. TACSTD2 is highly expressed in ovary, pancreas, and prostate as well as breast, for which Trop2-targeted therapy may be effective; however, oral, kidney, and skin cancers are not good examples for targeting Trop2 because TACSTD2 is overexpressed in normal tissues. Although normal breast and lung cases expressed TACSTD2 as well as tumor breast and lung cases, breast and lung tumors are highly heterogenous and the use of Trop2-targeted therapy is highly dependent on the subtypes for breast and lung cancers. Data was analyzed using TNMplot.com [80].

Figure 3

TACSTD2 expression in the different subtypes of breast cancer. TGCA breast cancer RNAseq data (FPKM) and phenotype data were downloaded from UCSC Xena (https://xena.ucsc.edu/), and the expression of TACSTD2 was analyzed using R, according to the result of IHC result of ER, PR and HER2. The data shows there is a significance difference between TNBC and Her2 positive breast cancer, but not between TNBC and ER positive breast cancer (One way ANOVA with post-hoc Tukey HSD test).

Figure 4

The mechanism of action of sacituzumab govitecan. Sacituzumab govitecan (SG) is the first ADC specifically approved for TNBC. There are three compartments in its structure: an anti-Trop2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload (SN-38). The antibody part targets the drug on Trop2 positive tumor cells and enhances Trop2 internalization. After the internalization of the ADC, the linker is cleaved by cathepsin and other proteolytic enzymes located at lysosome. SN-38 can then distribute into the nucleus of Trop2 positive and/or Trop2- neighboring tumor cells through the bystander killing effect. Therefore, SG is effective against heterogeneous cancer.