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

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.

Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness

“…An interesting mechanism by which TNBC tumours resist therapy is therapy-induced senescence (TIS) [ 73 ]. Senescence, or cellular growth arrest, is a cellular fate initially discovered in the context of cultured cells growth arrest and is now being recognised as an important mediator of numerous physiological and pathological processes [ 74 ].…”

“…It is believed that oncogene-induced senescence (OIS) is one of the contributing factors to TIS in numerous types of cancer, including mammary tumours [ 75 ]. Indeed, senescence can promote cancer stemness and tumour aggressiveness [ 76 ], with the stem-like state identified as the mediator for the development of drug-resistant aggressive clones within these tumours [ 73 ]. A study using matched pair gene expression analysis of 17 primary BC biopsies pre- and post-neoadjuvant chemotherapy revealed enrichment of TGF-β signatures, a cytokine that has been associated with breast CSCs in treated samples [ 77 ].…”

Proteomic characterisation of triple negative breast cancer cells following CDK4/6 inhibition

“…Inflammation via inflammatory cytokines secreted as part of the SASP also play an important role for tumour growth and survival 32 , 33 . On the other hand, senescence can promote an adaptive immune response and some SASP components may sensitise the cell state to combination therapies 24 , 32 , 34 , 35 . One such example is the combination therapy of an anti-PDL1 agent with Palbociclib, which is currently in clinical trials (PAveMenT, https://clinicaltrials.gov/ct2/show/NCT04360941/ ).…”

Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer

“…These include Wnt/β-catenin, Notch, Hedgehog, NFκB, PI3K/mTOR, Hippo/YAP, JAK/Stat, TGFβ, hypoxia, p53 loss of function and BRCA mutations, altered metabolism, and increased transporter and efflux pump activity [25,57,[62][63][64][65][66] . Single-cell sequencing has revealed that plasticity, heterogeneity, rapid molecular evolution of innate and acquired chemo-resistance, cellular senescence, and dynamic remodeling of epithelial-mesenchymal transition (TME)/mesenchymal-epithelial transition (MET) states of tumorinitiating cells or cancer stem cells in TNBC contribute to cancer recurrences [49,62,[67][68][69][70][71] . These aforementioned topics have been reviewed extensively in the TNBC literature.…”