Special Issue "Targeted Cancer Therapy and Mechanisms of Resistance"
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".
Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 17893
A printed edition of this Special Issue is available here.
Interests: Cancer; Kinase inhibitor; Target therapy; Signal transduction; Cell cycle; Mitogenesis; Survival; Resistance
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Tumor cells commonly exhibit dependence on a single (often the initiating) activated oncogenic pathway or protein to maintain their malignant proliferation and survival, a phenomenon that is called “oncogene addiction”. According to this concept, protein kinases have been elected as promising molecular targets for cancer therapy. There are several possibilities to target these proteins in cancer, including monoclonal antibodies that can bind to the extracellular domain of the RTK, compounds able to favor the proteolytic degradation of the kinase and, finally, small molecule protein kinase inhibitors (PKIs). In addition to targeting oncogenes, new anticancer treatments have been increasingly developed towards tumor suppressor genes and RNA interference.
Despite promising results in cancer treatment with targeted cancer drugs, clinical experience has shown that only a fraction of patients respond to targeted therapies, even if their tumor expresses the altered target. This kind of resistance is known as primary resistance. Moreover, secondary or acquired resistance to the treatment arises almost invariably when tumors are treated with cancer drugs. Acquired resistance mechanisms can be divided into two main categories: 1) target-dependent and 2) target-independent mechanisms.
Target-dependent resistance typically occurs through genetic modifications of the target. Such genetic modifications may include point mutations and copy number amplifications. The acquisition of mutations conferring drug resistance has been documented for several PKIs, such as drugs against BCR/ABL, EGFR, FLT3, KIT and PDGFR. Evidence suggests mutation may pre-exist in a minority of cancer cells, and it is then selected upon treatment. This suggests that secondary PKI that can also bind the mutated kinase can be used to overcome resistance. Gene amplification is another major mechanism of target-dependent resistance. The selective pressure of the drug can drive amplification of the target gene, thus leading to additional overexpression of the encoded protein.
Instead, target-independent mechanisms occur through activation of alternative pathways that allow the bypass of the drug-mediated block. In other words, cancer cells escape treatment by switching to an alternative signaling pathway that is not inhibited by the drug.
Other mechanisms of resistance can exploit the enormous genome plasticity of cancer cells by modulating miRNA expression or remodeling chromatin. Finally, though not as commonly as with classical cytotoxic drugs, other resistance mechanisms can cause a decrease of the effective intracellular concentration of the targeted cancer drug.
Prof. Dr. Valentina De Falco
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- kinase inhibitors
- animal model
- cell culture
- drug resistance
- signal transduction
- cell reprogramming
- clinical trials
- target therapy
- cancer heterogeneity
- stem cells
- cell cycle
- cell death inhibiting