CRITICAL REVIEWS IN ONCOGENESIS 2013 In Press
4. CONCLUSIONS AND FUTURE PERSPECTIVES
The availability of EGFR targeted agents has become an invaluable resource in the treatment of NSCLC, and the approval of gefitinib and erlotinib as first-line treatment of advanced NSCLC patients with EGFR activating mutations represents a milestone toward personalized medicine in medical oncology. However, most of these patients inevitably relapse due to the emergence of acquired resistance [4]. The challenge of tumor drug resistance to EGFR-TKIs makes multiple areas of research a priority, including assessment of novel biomarkers and possible targets that might prevent or suppress the proliferative, invasive and resistant behavior of lung cancer cells.
The understanding of the role exerted by specific miRNAs in the initiation and progression of lung cancer is exponentially increasing, but the knowledge about miRNAs affecting EGFR-TKIs resistance is still at an early stage. From previous studies on the role of miRNAs in resistance to conventional chemotherapy it is evident that, as with previous studies on gene profiling, most emerging miRNA signatures are not fully overlapping [42]. These difference might be explained by the type of specimens (frozen vs paraffin-embedded, micro- vs non-microdissected), experimental platforms used (quantitative PCR versus different miRNA array or in situ hybridization systems), tumor histology types, stage, regimens, small sample size, ethnic differences in the populations, lack of multivariate analysis and correction for multiple testing. In this regard, a general consensus is needed on the techniques and controls to be used and larger series of studies should be performed on paired neoplastic and normal tissues for NSCLC patients. Furthermore, the association of pathobiological with clinical information is warranted for the proper validation of specific miRNAs as new biomarkers.
The high stability of miRNAs in formalin-fixed or laser-microdissected tissues, and their expression levels, which can be directly measured also in blood, will increase their potential to contribute as diagnostic tool in lung cancer and, eventually, to identify responders and non-responders patients [43, 44].
An improved knowledge of the functions exerted by specific miRNAs in EGFR signaling pathways and
the precise identification of their key targets relevant to the resistance to EGFR-TKIs will also be instrumental for the development of miRNA-based therapeutics. Since miRNAs have the potential to modulate a cohort of gene networks, they might become therapeutically relevant in a “one-hit multitarget” context. The possibility to use miRNA agonists or antagonists, in order to restore/inhibit the function of down-regulated onco-suppressive miRNAs or upregulated oncogenic miRNAs, respectively, has been already successfully demonstrated in experimental tumor models. However, before translating experimental research advances into clinical practice, important issues mainly related to the development of new approaches for the in vivo delivery of miRNA-modulating molecules need to be addressed [45].
Hopefully, in the near future, the expression profiles of specific miRNAs could provide information about resistance of individual tumors to anti-EGFR treatments before starting therapy, whereas, the modulation of the expression of specific miRNAs before and during treatment might offer a new tool to overcome drug resistance and thereby improve the clinical outcome of NSCLC patients.
ACKNOWLEDGEMENTS
This work was supported by grants from the Netherlands Organization for Scientific Research (NWO, Veni grant, Elisa Giovannetti), AIRC-Marie Curie (International Fellowship, Elisa Giovannetti), CCA-VICI foundation (grant#2012-5-07, Amir Avan, Godefridus J. Peters, Elisa Giovannetti), FIRC grant (Fellowship for abroad, Elena Galvani).
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