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MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours

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Abstract

Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18–22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours.

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Acknowledgements

The authors would like to thank Ms. Kate Eason very much for her great help and support during the preparation of this manuscript, especially for language editing.

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  1. Michele Ghidini and Jens C. Hahne contributed equally to this work.

Authors and Affiliations

  1. Medical Department, Division of Oncology, ASST di Cremona, Ospedale di Cremona, Cremona, Italy

    Michele Ghidini, Gianluca Tomasello & Rodolfo Passalacqua

  2. Centre for Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK

    Jens C. Hahne, Andrea Lampis & Nicola Valeri

  3. Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK

    Melissa Frizziero

  4. Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Francesco Trevisani

  5. The Royal Marsden NHS Foundation Trust, London, UK

    Nicola Valeri

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  1. Michele Ghidini
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Correspondence to Jens C. Hahne.

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Michele Ghidini, Jens C. Hahne, Melissa Frizziero, Gianluca Tomasello, Francesco Trevisani, Andrea Lampis, Rodolfo Passalacqua, and Nicola Valeri declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

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Ghidini, M., Hahne, J.C., Frizziero, M. et al. MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours. Targ Oncol 13, 423–436 (2018). https://doi.org/10.1007/s11523-018-0580-3

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