Triple negative breast cancer (TNBC) is classically treated with
combination chemotherapies. Although, initially responsive to
chemotherapies, TNBC patients frequently develop
drug-resistant, metastatic disease.
Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the
therapy-induced senescence (TIS). In this paper, we will focus on chemoresistance in TNBC due to TIS. One of the key characteristics of senescent cells is a complex secretory phenotype, known as the senescence-associated secretory
proteome (SASP), which by prompting immune-mediated clearance of senescent cells maintains tissue homeostasis and suppresses
tumorigenesis. However, in
cancer, particularly with TIS, senescent cells themselves as well as SASP promote cellular reprograming into a stem-like state responsible for the emergence of
drug-resistant, aggressive clones. In addition to
chemotherapies, outcomes of recently approved immune and DNA damage-response (DDR)-directed
therapies are also affected by TIS, implying that this a common strategy used by
cancer cells for evading treatment. Although there has been an explosion of scientific research for manipulating TIS for prevention of drug resistance, much of it is still at the pre-clinical stage. From an evolutionary perspective,
cancer is driven by natural selection, wherein the fittest
tumor cells survive and proliferate while the tumor microenvironment influences
tumor cell fitness. As TIS seems to be preferred for increasing the fitness of
drug-challenged
cancer cells, we will propose a few tactics to control it by using the principles of evolutionary biology. We hope that with appropriate therapeutic intervention, this detrimental cellular fate could be diverted in favor of TNBC patients.