Targeting Triple-Negative Breast Cancer: Resistance Mechanisms and Therapeutic Advancements

Abstract

Background: Triple-negative breast cancer (TNBC) is one of the most heterogeneous and menacing forms of breast cancer, with no sustainable cure available in the current treatment landscape. Its lack of targets makes it highly unresponsive to various treatment modalities, which is why chemotherapy continues to be the primary form of treatment, despite the high rates of patients developing chemoresistance. In recent years, however, there has been significant progress in identifying and understanding the role of several aspects that might contribute to genomic instability and other hallmarks of cancer, including cellular proteins, immune targets, and epigenetic mechanisms, which are desirable as they permit reversibility easier than the often-adamant genetic changes.

Methods: A literature review was conducted on the role of various TNBC associated biomarkers, their therapeutic applications, and their role in tumorigenesis and tumor maintenance, with a focus on linking both the driving biological mechanisms and emerging treatment options for TNBC.

Conclusions: Shifting the focus of treatment to identify crucial tumor cell subpopulations and associated biomarkers, such as local immune cell populations and cancer stem cells, could potentially solve or simplify decades' worth of problems that are associated with TNBC, bolstering early detection and the evolution of precision medicine and treatment. The techniques that can be used here are epigenetic analysis and RNA sequencing. Biomarkers, such as PD-L1, survivin, and ABC transporters, are implicated in several crucial processes that maintain tumors, such as cell proliferation, metastasis, immunosuppression, and stemness. Complex treatment options such as, immunotherapy, pathway inhibition, PARP inhibition, virotherapy, and RNA targeting have been considered for TNBC. Phytochemicals are also being considered as a treatment modality for TNBC, as a supplement to chemotherapy and radiation therapy, or as sole treatment.

Keywords: biomarkers; cancer stem cells; phytochemicals; plasticity; single‐cell RNA sequencing; tumor microenvironment.

FIGURE 1

Overview of targeted cellular signaling pathways in TNBC. Various cellular signaling pathways can be targeted for the treatment of TNBC. Modes of inhibition include inhibition of receptor‐ligand binding, disruption of protein assembly, and interference with tumor signaling mechanisms, resulting in reduced cellular proliferation, reduced metastasis, and reduced tumor growth.

FIGURE 2

Overview of various cellular targets and therapies for TNBC. Cellular targets for TNBC treatment include signaling pathways, immune checkpoint molecules/receptors, RNAs, sites of epigenetic modifications, and PARPs. Small molecules, monoclonal antibodies, oncolytic viruses, and chemotherapy drugs are among the several treatment systems that can be used to target different components and processes in tumor cells.

FIGURE 3

Phytochemicals used for TNBC treatment and their cellular targets. Phytochemicals have been shown to play an important role in future treatments for TNBC. Plant compounds and their derivatives may be used alone or in conjunction with standard treatments, such as chemotherapeutic drugs, to treat TNBC. Phytochemicals are capable of reducing metastasis, inducing apoptosis by triggering the required cascades and inducing ROS accumulation, and inhibiting the activation of cellular signaling pathways.