Guest Editors
Valentina De Falco, Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Naples, Italy. E-mail: valentina.defalco@ieos.cnr.it
Maria Letizia Motti, Department of Movement Sciences and Wellbeing, University “Parthenope”, Naples, Italy. Email: letizia.motti@uniparthenope.it
Summary
Tumor cells commonly exhibit dependence on a single oncogenic pathway or activated protein (often the initiating one) to maintain their malignant proliferation and survival, a phenomenon called “oncogene addiction.” According to this concept, kinases have been elected as promising molecular targets for cancer therapy. There are several possibilities for targeting these proteins in cancer, including monoclonal antibodies that can bind to the extracellular domain of the RTK, compounds that can promote the proteolytic degradation of the kinase, and finally, small molecule protein kinase inhibitors (PKIs). In addition to targeting oncogenes, new anticancer treatments have increasingly been developed targeting tumor suppressor genes and other circuits involved in supporting oncogenic pathways.
Despite promising results in the treatment of cancer with targeted anticancer drugs, clinical experience has shown that in fact only a fraction of patients respond to targeted therapies. This type of resistance is known as primary resistance. Furthermore, when tumors are treated with anticancer drugs, secondary (or acquired) resistance to treatment often develops. Acquired resistance mechanisms can be divided into two main categories: (1) target-dependent mechanisms and (2) target-independent mechanisms.
Target-dependent resistance typically occurs through genetic modifications of the target. Such genetic changes can include point mutations and copy number amplifications. The acquisition of mutations conferring drug resistance has been documented for several PKIs, with evidence suggesting that the mutation may pre-exist in a minority of tumor cells and is therefore selected for during treatment. This suggests that secondary PKI that can also bind the mutated kinase can be used to overcome resistance. Gene amplification is another important target-dependent resistance mechanism. The selective pressure of the drug can drive amplification of the target gene, thus leading to further overexpression of the encoded protein.
Instead, target-independent mechanisms occur through the activation of alternative pathways that allow bypass of drug-mediated blockade. In other words, tumor cells escape treatment by switching to an alternative signaling pathway that is not inhibited by the drug.
This special issue seeks to bring together a series of original research articles and updated reviews spanning all aspects of precision medicine through the identification of novel targets in tumor oncology. Work that helps decipher molecular changes and identify biomarkers and predictors of prognosis, as well as advances in therapeutic options with the identification of resistance mechanisms, are central topics, as are contributions on other significant topics that further improve our understanding of the molecular immunotherapy and all targeted anti-tumor therapies.
Keywords
cancer
kinase inhibitors
animal model
cell culture
drug resistance
signal transduction
survival
cell reprogramming
pathways
clinical trials
target therapy
cancer heterogeneity
stem cells
immunity
cell cycle
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