Hallmarks of cancer resistance

Abstract

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.

Keywords: biological sciences; cancer; epigenetics; health sciences; microenvironment; molecular biology.

Graphical abstract

Figure 1

Genomic instability in cancer biology and therapy resistance The figure illustrates the pivotal role of genomic instability in cancer biology and therapy resistance. Genomic instability, triggered by factors such as radiation, chemicals, and environmental stressors, leads to DNA damage and subsequent activation of DNA damage response (DDR) signaling pathways. This genomic turmoil results in various genetic alterations, including mutations, chromosomal rearrangements, and copy number variations. These alterations contribute to the initiation and progression of cancer. Furthermore, genomic instability plays a crucial role in therapy resistance by promoting the generation of resistance mutations and activating bypass signaling pathways.

Figure 2

Dynamics of the tumor microenvironment (TME) in cancer tissues The figure illustrates the intricate dynamics of the tumor microenvironment (TME) within cancer tissues. The TME is divided into two main sections: immune cells serving as architects of restraint, such as Tumor-Infiltrating Lymphocytes (TILs), cytotoxic T cells, and Natural Killer (NK) cells, and immune cells facilitating cancer growth, including Myeloid-Derived Suppressor Cells (MDSCs), M2-polarized Tumor-Associated Macrophages (TAMs), and Regulatory T Cells (Tregs). TILs, primarily composed of T cells, are associated with favorable prognoses and enhanced immunotherapy effectiveness. NK cells, with their ability to directly target cancer cells, play a crucial role in immune surveillance, but their activity is inhibited in the hypoxic and acidic TME, leading to resistance. Cytotoxic T cells are central in identifying and eliminating cancer cells, connecting to CAR-T cell therapy. MDSCs, elevated in the TME, create an immunosuppressive microenvironment promoting resistance. M2-polarized TAMs foster an immunosuppressive milieu, contributing to resistance. Tregs maintain immune tolerance, dampening anti-tumor responses and promoting resistance. The figure also depicts an interaction network between immune cells and highlights the influence of cytokines such as VEGF, GM-CSF, M-CSF, and G-CSF on immune cell behavior in the TME.

Figure 3

Clinical trials targeting RTKs signaling to overcome cancer resistance This figure illustrates about the clinical trials for targeting RTKs signaling to overcome cancer resistance.

Figure 4

Clinical trial targeting the Wnt pathway to combat cancer resistance This figure illustrates the clinical trial targeting the Wnt pathway to combat cancer resistance.

Figure 5

Interplay of Bcl-2 family proteins and therapeutic intervention in cancer resistance This illustration depicts the intricate interplay of Bcl-2 family proteins and the disrupted equilibrium in cancer cells leading to apoptosis resistance. The structure of Bcl-2 family proteins is delineated, showcasing pro-apoptotic members, alongside their anti-apoptotic counterparts. Disruptions in equilibrium, emanate from sources such as genetic mutations, gene amplifications, and aberrant protein expression, underscoring the multifaceted nature of cancer resistance. The targeted inhibitors, venetoclax, ABT-737, and Navitoclax, are elucidated with lines pointing to their respective positions. Venetoclax, ABT-737, and Navitoclax act through distinct mechanisms, inhibiting anti-apoptotic proteins or promoting pro-apoptotic activities, ultimately restoring apoptosis in cancer cells. This figure illustrates the critical role of Bcl-2 family proteins, the perturbations in their equilibrium, and the therapeutic interventions aimed at overcoming cancer resistance through targeted inhibition.

Figure 6

Mitochondrial biology and implications in cancer resistance This figure discusses various aspects of mitochondrial biology and their implications in cancer resistance. Mitochondrial components such as the inner membrane, mtDNA, mitochondrial ribosomes, mitochondrial matrix, endoplasmic reticulum, and cristae play crucial roles in cancer cell adaptation and resistance to therapies. The inner membrane’s modulation of oxidative phosphorylation (OXPHOS) influences cancer cell responses to metabolic-targeted therapies and resistance against oxidative stress-induced cell death. mtDNA mutations impact tumor initiation and chemoresistance, contributing to cancer heterogeneity and altering treatment responses. Mitochondrial ribosomes are essential for protein synthesis crucial to energy metabolism and are linked to drug resistance in various cancers. The mitochondrial matrix is central to energy production, metabolism, redox homeostasis, and apoptotic pathways, shaping cancer cell resistance. The endoplasmic reticulum influences cellular functions, mitochondrial dynamics, apoptosis regulation, and stress resistance in cancer cells. Mitochondrial cristae, integral to maintaining mitochondrial membrane potential and influencing ATP synthesis and apoptosis regulation, may impact cancer cell resistance to apoptotic stimuli and certain therapies. This figure also outlines various strategies for targeting mitochondria in cancer cells to induce apoptosis, disrupt energy metabolism, and overcome resistance. These include mitochondrial uncouplers, electron transport chain inhibitors, ROS-inducing agents, modulation of the mitochondrial permeability transition pore, stimulation of mitophagy, targeting mitochondrial DNA replication, HSP90 inhibitors, peptide-based therapies, and photodynamic therapy. These strategies exploit specific vulnerabilities, offering potential therapeutic avenues, requiring further research to optimize and assess clinical applicability.

Figure 7

Integrated therapeutic approaches in cancer treatment The figure illustrates integrated therapeutic approaches in cancer treatment, highlighting key strategies. Targeted therapies involve the combination of chemotherapy and targeted agents to simultaneously address rapidly dividing cancer cells, utilizing chemotherapy, and disrupt specific signaling pathways, deploying targeted therapies. Immunotherapies focus on immune checkpoint inhibitors such as pembrolizumab and nivolumab, blocking signals for immune evasion, and CAR-T cell therapy for haematological malignancies. Combination therapies synergize to enhance anti-cancer responses and potent suppression of cancer growth. Personalized treatment involves molecular profiling to identify genetic alterations, tailoring treatment based on individual tumor profiles, and maximizing therapeutic efficacy through personalized regimens. This integrated approach harnesses the strengths of targeted therapies, immunotherapies, and personalized treatment, offering a comprehensive strategy against cancer.