Mechanism of cell adaptation: when and how do cancer cells develop chemoresistance?

Abstract

Chemotherapy treatments are considered essential tools to defeat cancer progression and dissemination to improve patients' quality of life and survival. Although most malignancies initially respond to chemotherapeutic treatments, after an unpredictable period, tumor cells develop mechanisms of resistance to the treatment. Different cell compartments are involved in the mechanism of chemoresistance, and multiple mechanisms can be activated by single cells at different times of the cancer progression. Alteration of drug metabolism, derangement of intracellular pathways' signaling, cross-talk between different membrane receptors, and modification of apoptotic signaling and interference with cell replication are all mechanisms that the cell uses to overcome the effect of pharmacological compounds.In this review, we describe different adaptation, mostly at the level of the proteome, which cancer cells use to develop resistance to cancer treatment.

FIGURE 1

Schematic representation of the main cellular mechanisms of chemioresistance. Efficacy of anticancer drugs is driven by multiple factors that go from alteration of drug processing to the regulation of the main pathway involved in cell survival and proliferation. During drug processing, different conditions favor alteration in drug uptake and export. Genetic variants of enzymes involved in drug processing reduce activation or enhance inactivation. Genetic mutations affect drug target genes causing modifications in drug-target interaction. Cancer cells respond to stress conditions by activating feedback pathway that keep them alive, such as enhanced proliferation signal (by epidermal growth factor receptor and mitogen-activated protein kinase/ extracellular single-regulated kinase pathway), deranged DNA repair mechanisms, and inhibition of apoptosis. All of these are mechanisms that counteract drugs’ action, making the cell resistant to them.