Unveiling the vulnerabilities of synthetic lethality in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most invasive molecular subtype of breast cancer (BC), accounting for about nearly 15% of all BC cases reported annually. The absence of the three major BC hormone receptors, Estrogen (ER), Progesterone (PR), and Human Epidermal Growth Factor 2 (HER2) receptor, accounts for the characteristic Triple negative phraseology. The absence of these marked receptors makes this cancer insensitive to classical endocrine therapeutic approaches. Hence, the available treatment options remain solemnly limited to only conventional realms of chemotherapy and radiation therapy. Moreover, these therapeutic regimes are often accompanied by numerous treatment side-effects that account for early distant metastasis, relapse, and shorter overall survival in TNBC patients. The rigorous ongoing research in the field of clinical oncology has identified certain gene-based selective tumor-targeting susceptibilities, which are known to account for the molecular fallacies and mutation-based genetic alterations that develop the progression of TNBC. One such promising approach is synthetic lethality, which identifies novel drug targets of cancer, from undruggable oncogenes or tumor-suppressor genes, which cannot be otherwise clasped by the conventional approaches of mutational analysis. Herein, a holistic scientific review is presented, to undermine the mechanisms of synthetic lethal (SL) interactions in TNBC, the epigenetic crosstalks encountered, the role of Poly (ADP-ribose) polymerase inhibitors (PARPi) in inducing SL interactions, and the limitations faced by the lethal interactors. Thus, the future predicament of synthetic lethal interactions in the advancement of modern translational TNBC research is assessed with specific emphasis on patient-specific personalized medicine.

Automated summary

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer characterized by the absence of estrogen, progesterone, and HER2 receptors. This makes TNBC insensitive to traditional endocrine therapies. Current treatment options are limited to chemotherapy and radiation therapy, which often have side effects and lead to poor outcomes. Synthetic lethality, a promising approach that targets undruggable genes, such as oncogenes or tumor suppressor genes, could offer new treatment opportunities for TNBC. This review explores the mechanisms of synthetic lethal interactions in TNBC, the role of PARP inhibitors in inducing these interactions, and the limitations faced by synthetic lethal interactors, with a focus on personalized medicine for TNBC patients.