Understanding and targeting resistance mechanisms in cancer

Abstract

Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.

Keywords: cancer therapy; combination therapy; drug resistance; resensitization.

FIGURE 1

Cancer resistance mechanisms, including drug inactivation, insufficient intracellular drug concentration, drug target alterations, compensatory pathways activation, DNA repair enhancement, and tumor plasticity. Source: This figure was created with Biorender.com.

FIGURE 2

Alteration of drug target and activation of compensating pathways. Cancer resistance associated with alterations in the drug target site or modifications in the structure of the target. The reactivation of the downstream pathway bypasses the other unblocked pathway enabling drug resistance. Activation of compensatory signaling pathways to resist cell death leading to drug resistance. Source: This figure was created with Biorender.com.

FIGURE 3

Adaptive mechanisms of cancer cell survival and cancer resistance driven by tumor microenvironment (TME). The TME is important for cancer resistance; the cancer cells within the TME can undergo a series of adaptive changes, such as various cellular components can complement the growth signal of cancer cells, combining with angiogenesis to promote cell survival and resistance. The immunosuppression caused by the TME prevents immune cells from killing cancer cells. The induction of the TGF‐β signaling and the release of prostaglandin E2 (PGE2) resulting in further augmentation of self‐renewal and plasticity of cancer stem cells (CSCs). Source: This figure was created with Biorender.com.

FIGURE 4

Overcoming drug resistance in cancer. The purpose of overcoming the drug resistance of cancer cells is to optimize the sensitivity of the therapy. This can be achieved by polytherapy using the combination of at least two drugs; immunotherapy using checkpoint inhibitors or monoclonal antibodies; antibody–drug–conjugates improving the selectivity of cancer treatment; gene technology modifying the epigenetic sequence; targeted therapy targeting the overexpression of drug efflux transporter or vital proteins for the cancer cell apoptosis; and nanoparticle delivery system improving the efficacy of the drug and reducing the side effect. Source: This figure was created with Biorender.com.