Abstract
The advent of precision therapies against specific gene alterations characterizing different neoplasms is revolutionizing the oncology field, opening novel treatment scenarios. However, the onset of resistance mechanisms put in place by the tumor is increasingly emerging, making the use of these drugs ineffective over time. Therefore, the search for indicators that can monitor the development of resistance mechanisms and above all ways to overcome it, is increasingly important. In this scenario, microRNAs are ideal candidate biomarkers, being crucial post-transcriptional regulators of gene expression with a well-known role in mediating mechanisms of drug resistance. Moreover, as microRNAs are stable molecules, easily detectable in tissues and biofluids, they are the ideal candidate biomarker to identify patients with primary resistance to a specific targeted therapy and those who have developed acquired resistance. The aim of this review is to summarize the major studies that have investigated the role of microRNAs as mediators of resistance to targeted therapies currently in use in gastro-intestinal neoplasms, namely anti-EGFR, anti-HER2 and anti-VEGF antibodies, small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors. For every microRNA and microRNA signature analyzed, the putative mechanisms underlying drug resistance were outlined and the potential to be translated in clinical practice was evaluated.
Highlights
The number of druggable tumor-specific molecular alterations has grown substantially in the past decade and a great survival benefit has been obtained from genomic-driven therapies across many cancer types
Cappuzzo et al found that the high-intensity signature of the cluster Let-7c/miR-99a/miR-125b is associated with a favorable response to cetuximab and panitumumab in KRAS wild-type metastatic colorectal cancer (mCRC) patients [32]
Vascular endothelial growth factor (VEGF) or VEGFR, soluble VEGF receptors, and tyrosine kinase inhibitors selective for Bevacizumab is a monoclonal antibody directed against VEGF and has been approved in combination with cytotoxic chemotherapy as first or second-line therapy in mCRC, after several randomized clinical trials had shown improvements in overall survival [43,44,45]
Summary
The number of druggable tumor-specific molecular alterations has grown substantially in the past decade and a great survival benefit has been obtained from genomic-driven therapies across many cancer types. Primary or intrinsic resistance is defined as radiographic or clinical disease progression as the best response to an anticancer therapy and implies the pre-existence of resistancemediating factors within the tumor [2]. 2 of 19 diseas progression as the best response to an anticancer therapy and implies the pre-existence o resistance-mediating factors within the tumor [2]. A wide range of biological determinants have been associated with drug resistance to targeted therapies; these include the presence of undruggable genomic drivers, th to targeted therapies; these include the presence of undruggable genomic drivers, the mutation of drug targets, the activation of survival signaling pathways, and th mutation of drug targets, the activation of survival signaling pathways, and the inactivation inactivation of downstream death signaling pathways.
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