Death-ision: the link between cellular resilience and cancer resistance to treatments

Abstract

One of the key challenges in defeating advanced tumors is the ability of cancer cells to evade the selective pressure imposed by chemotherapy, targeted therapies, immunotherapy and cellular therapies. Both genetic and epigenetic alterations contribute to the development of resistance, allowing cancer cells to survive initially effective treatments. In this narration, we explore how genetic and epigenetic regulatory mechanisms influence the state of tumor cells and their responsiveness to different therapeutic strategies. We further propose that an altered balance between cell growth and cell death is a fundamental driver of drug resistance. Cell death programs exist in various forms, shaped by cell type, triggering factors, and microenvironmental conditions. These processes are governed by temporal and spatial constraints and appear to be more heterogeneous than previously understood. To capture the intricate interplay between death-inducing signals and survival mechanisms, we introduce the concept of Death-ision. This framework highlights the dynamic nature of cell death regulation, determining whether specific cancer cell clones evade or succumb to therapy. Building on this understanding offers promising strategies to counteract resistant clones and enhance therapeutic efficacy. For instance, combining DNMT inhibitors with immune checkpoint blockade may counteract YAP1-driven resistance or the use of transcriptional CDK inhibitors could prevent or overcome chemotherapy resistance. Death-ision aims to provide a deeper understanding of the diversity and evolution of cell death programs, not only at diagnosis but also throughout disease progression and treatment adaptation.

Fig. 1

Genomic and epigenomic modifications concurrently contribute to the response to anticancer treatments. Bulk tumor masses are composed of cancer cells with diverse genomic alterations and epigenetic landscapes. Under treatment pressure, tolerant or persistent cells are selected as those in which specific genomic and epigenomic changes confer a survival advantage. These selected clones can expand, leading to drug-resistant tumor relapse. The same epigenetic state may either support or hinder treatment efficacy, depending on the underlying genomic context and the microenvironmental niche in which the cancer cells reside

Fig. 2

Key steps from initiated cell of origin to invasive cancer development. Carcinogenesis is an inefficient process where the evolution of initiated cells into the appearance of a locally invasive cancer is the balance between tumor promoting (red) and opposing (green) factors. In the image some of the key players involved are depicted. It is noteworthy that in this process the crosstalk between the initiated/transformed cells and the host local environment plays a central role; with the host controlling tumor evolution (e.g. tissue restraining factors or immune control) and cancer cells directly influencing the surrounding environment (e.g. transforming fibroblast to CAF etc.)

Fig. 3

Epigenetics in drug resistance. Epigenetic modifications contribute to drug resistance in cancer cells by altering gene expression profiles. The mechanisms include DNA methylation, hydroxymethylation, nucleosome repositioning, histone modifications, and the regulation of non-coding RNAs. These changes enable cancer cells to develop diverse strategies to evade the effects of cancer therapeutics. In the figure several examples on how epigenetic modifications impact the response to different anti-cancer treatments is shown (see text for more details)

Fig. 4

Relation between RCD and senescence, autophagy and mitotic catastrophe. Cancer cells are subjected to different conditions that can trigger cell death from inflammation to environmental stress. Anticancer treatments are also potent death inducers of RCD. Within the same cell, several cell death programs co-exist and are triggered by specific signals such as DNA damage for apoptosis; inflammation for pyroptosis, dysregulated lipids oxidations for ferroptosis; TNF stimulation for necroptosis. Some programs such as entosis or PANoptosis exhibit features common with different of RCD. Alternative RCD can relay the main cell death program if it is deficient. It is not known if the activation of RCD replacement is due to specific mechanisms or co-induction at the time of the primary stimulus. More likely, since some components are common between several RCD (major genes implicated in the different pathways) and a crossover between RCD might be common in most cases

Fig. 5

Cell Death-ision. Graphical representation of the Death-ision process in which from a heterogenous drug-sensitive tumor mass (green background in the gradient color scale) drug resistant clones could emerge (red background in the gradient color scale). Cell stress is induced by external stimuli (such as treatments) in the different cancer cells populations (clones, cancer stem cells and drug tolerant/persistent) (stage 1). Depending on the nature and/or duration of the signal, stress can lead to the elimination of cancer cells through ACD, specific or combinations of RCD (stage 2). Non-responding cells can be cancer stem cells, pre-existing resistant clones or drug tolerant/persistent cells (stage 3). Cancer can survive as slow cycling cancer cells (stage 4) or acquire resistant mechanisms (stage 5). Resistant clones can either proliferate (high fitness resistant cells (stage 6) or, for some subpopulations (low fitness resistant cells) die or become slow cycling dormant cells (stage 7). Depending on external signal, dormant cells can re-enter a proliferation stage to become aggressive metastatic or recurrent cancers (stage 8). The dying or survival of cancer cells can be affected by the microenvironment which can facilitate tumor resistance and growth through various stages. The purpose of death-ision is to determine when and how cells survive in order to provide stage specific treatments