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Drug resistance in pituitary tumours: from cell membrane to intracellular signalling

Abstract

The pharmacological treatment of pituitary tumours is based on the use of stable analogues of somatostatin and dopamine. The analogues bind to somatostatin receptor types 2 and 5 (SST2 and SST5) and dopamine receptor type 2 (DRD2), respectively, and generate signal transduction cascades in cancerous pituitary cells that culminate in the inhibition of hormone secretion, cell growth and invasion. Drug resistance occurs in a subset of patients and can involve different steps at different stages, such as following receptor activation by the agonist or during the final biological responses. Although the expression of somatostatin and dopamine receptors in cancer cells is a prerequisite for these drugs to reach a biological effect, their presence does not guarantee the success of the therapy. Successful therapy also requires the proper functioning of the machinery of signal transduction and the finely tuned regulation of receptor desensitization, internalization and intracellular trafficking. The present Review provides an updated overview of the molecular factors underlying the pharmacological resistance of pituitary tumours. The Review discusses the experimental evidence that supports a role for receptors and intracellular proteins in the function of SSTs and DRD2 and their clinical importance.

Key points

  • Pharmacological treatment of pituitary tumours targets somatostatin receptor type 2, somatostatin receptor type 5 and dopamine receptor type 2; these receptors generate signal transduction cascades that culminate in the inhibition of hormone secretion, cell growth and invasion.

  • The success of pharmacological therapy requires proper functioning of the machinery of signal transduction and finely tuned regulation of receptor desensitization, internalization and intracellular trafficking.

  • Although the expression of somatostatin and dopamine receptors in cancer cells has been associated with better responsiveness, a clear conclusion about the possible use of the receptor expression profile to predict medical outcome has not been reached.

  • Drug resistance can involve different steps at different stages following receptor activation; a variety of molecules, including G proteins, AIP, β-arrestins, filamin A, E-cadherin, USP8 and specific microRNAs, might affect the efficacy of therapy.

  • None of the molecules downstream of somatostatin and dopamine receptor activation are currently used in clinical practice as prognostic biomarkers for patient selection and management.

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Fig. 1: SST and DRD2 classical signalling pathways.
Fig. 2: Role of FLNA in regulating SST2 and DRD2 expression on cell surface and function in PitNET cells.

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Acknowledgements

The authors acknowledge the support of AIRC (Associazione Italiana Ricerca Cancro) grant to G.M. (IG 2017-20594), the Italian Ministry of Health grant to G.M. (PE-2016-02361797), Ricerca Corrente Funds from the Italian Ministry of Health and Progetti di Ricerca di Interesse Nazionale (PRIN) grant to E.P. (2017N8CK4K).

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Peverelli, E., Treppiedi, D., Mangili, F. et al. Drug resistance in pituitary tumours: from cell membrane to intracellular signalling. Nat Rev Endocrinol 17, 560–571 (2021). https://doi.org/10.1038/s41574-021-00514-0

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