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Review
. 2021 Jun 24:11:674354.
doi: 10.3389/fonc.2021.674354. eCollection 2021.

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

Anindita Chakrabarty  1 , Shayantani Chakraborty  1 , Ranjini Bhattacharya  1 , Goutam Chowdhury  2
Affiliations
Review

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies

Anindita Chakrabarty et al. Front Oncol. .

Abstract

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.

Keywords: adaptive therapy; chemotherapy; evolution; senescence; senescence-associated stemness; therapy-induced senescence; triple negative breast cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of types of senescence.
Figure 2
Figure 2
Schematic representation of conventional and adaptive treatment strategies and their outcomes in triple negative breast cancers. (A) Relapse of drug-resistant tumors due to conventional chemotherapy-induced senescence in TNBC patients. (B) Adaptive therapeutic strategies to combat chemotherapy-induced senescence in TNBC.
See this image and copyright information in PMC

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