Mechanisms and insights into drug resistance in cancer

Abstract

Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.

Cancer stem cells and addicted cancer cells

“…The long-term effect of imatinib can be altered due to mutations occurring at gatekeeper residues of the kinase domains. These mutations result in the inability of imatinib to bind to its target site and consequently lead to resistance of the cells [113]. Cancer cells can also avoid the effects of drugs by amplification of other oncogenes or inactivation of alternative survival pathways [113].…”

“…Besides oncogene addiction and hypersensitivies, stem-cell like properties of a small subset of cancer cells also help tumors to become resistant to anticancer agents [112]. CSCs are thought to survive drug-induced selection pressures, ultimately leading to subpopulations that contribute to cancer relapse [113]. Patients with the 'same' cancer often respond differently to the same treatment, based on the extensive variation in the different genes that are mutated, the nature of these mutations and their consequences for the behavior of the cancer cells.…”

“…These mutations result in the inability of imatinib to bind to its target site and consequently lead to resistance of the cells [113]. Cancer cells can also avoid the effects of drugs by amplification of other oncogenes or inactivation of alternative survival pathways [113]. In addition, the evasion of apoptotic pathways by mutations that inactive genes that normally code for apoptotic proteins, such as p53, or activating mutations in genes that code for anti-apoptotic proteins, such as BCL-2, can also result in resistance [113].…”

“…Cancer cells can also avoid the effects of drugs by amplification of other oncogenes or inactivation of alternative survival pathways [113]. In addition, the evasion of apoptotic pathways by mutations that inactive genes that normally code for apoptotic proteins, such as p53, or activating mutations in genes that code for anti-apoptotic proteins, such as BCL-2, can also result in resistance [113]. Besides oncogene addiction and hypersensitivies, stem-cell like properties of a small subset of cancer cells also help tumors to become resistant to anticancer agents [112].…”

“…For example, small molecule drug imatinib has been developed to target BCR/ABL tyrosine kinase in CML. Other tyrosine kinase inhibitors like gefitinib and erlotinib specifically target epidermal growth factor receptor (EGFR) tyrosine kinase domains in non-small cell lung carcinoma [113].…”