Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Endocrinology volume 17, pages 560–571 (2021)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Osamura, R. Y. in WHO Classification of Tumours of Endocrine Organs (eds Lloyd, R. V., Osamura, R. Y., Klöppel, G. & Rosai, J.) Ch. 1. 14–18 (WHO, 2017).

  2. Trouillas, J. et al. How to classify pituitary neuroendocrine tumors (PitNET)s in 2020. Cancers 12, 514 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  3. Melmed, S. Pituitary-tumor endocrinopathies. N. Engl. J. Med. 382, 937–950 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Bauer, W. et al. SMS 201–995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 31, 1133–1140 (1982).

    Article  CAS  PubMed  Google Scholar 

  5. Bruns, C., Lewis, I., Briner, U., Meno-Tetang, G. & Weckbecker, G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrinol. 146, 707–716 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Katznelson, L. et al. Acromegaly: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 99, 3933–3951 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Colao, A. et al. Acromegaly. Nat. Rev. Dis. Prim. 5, 20 (2019).

    Article  PubMed  Google Scholar 

  8. Freda, P. U. et al. Long-acting somatostatin analog therapy of acromegaly: a meta-analysis. J. Clin. Endocrinol. Metab. 90, 4465–4473 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Giustina, A. et al. Meta-analysis on the effects of octreotide on tumor mass in acromegaly. PLoS ONE 7, e36411 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Colao, A. et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N. Engl. J. Med. 366, 914–924 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Gadelha, M. R. et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2, 875–884 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Melmed, S. et al. Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 273–288 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Møller, L. N., Stidsen, C. E., Hartmann, B. & Holst, J. J. Somatostatin receptors. Biochim. Biophys. Acta 1616, 1–84 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Taboada, G. F. et al. Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur. J. Endocrinol. 158, 295–303 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Vitali, et al. Cyclic adenosine 3′-5′-monophosphate (cAMP) exerts proliferative and anti-proliferative effects in pituitary cells of different types by activating both cAMP-dependent protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac). Mol. Cell. Endocrinol. 383, 193–202 (2014).

    Article  CAS  Google Scholar 

  16. Peverelli, E., Mantovani, G., Lania, A. & Spada, A. cAMP in the pituitary: an old messenger for multiple signals. J. Mol. Endocrinol. 52, R67–R77 (2013).

    Article  PubMed  CAS  Google Scholar 

  17. Peverelli, E. et al. Specific roles of G(i) protein family members revealed by dissecting SST5 coupling in human pituitary cells. J. Cell Sci. 126, 638–644 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Florio, T. Somatostatin/somatostatin receptor signalling: phosphotyrosine phosphatases. Mol. Cell. Endocrinol. 286, 40–48 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Ferrante, E. et al. Octreotide promotes apoptosis in human somatotroph tumor cells by activating somatostatin receptor type 2. Endocr. Relat. Cancer 13, 955–962 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Peverelli, E. et al. Filamin A (FLNA) plays an essential role in somatostatin receptor 2 (SST2) signaling and stabilization after agonist stimulation in human and rat somatotroph tumor cells. Endocrinology 155, 2932–2941 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Vázquez-Borrego, M. C. et al. A somatostatin receptor subtype-3 (SST3) peptide agonist shows antitumor effects in experimental models of nonfunctioning pituitary tumors. Clin. Cancer Res. 26, 957–969 (2020).

    Article  PubMed  Google Scholar 

  22. Peverelli, E. et al. A novel pathway activated by somatostatin receptor type 2 (SST2): inhibition of pituitary tumor cell migration and invasion through cytoskeleton protein recruitment. Int. J. Cancer 142, 1842–1852 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Missale, C., Nash, S. R., Robinson, S. W., Jaber, M. & Caron, M. G. Dopamine receptors: from structure to function. Physiol. Rev. 78, 189–225 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Iaccarino, C. et al. Control of lactotrop proliferation by dopamine: essential role of signaling through D2 receptors and ERKs. Proc. Natl Acad. Sci. USA 99, 14530–14535 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hayes, G., Biden, T. J., Selbie, L. A. & Shine, J. Structural subtypes of the dopamine D2 receptor are functionally distinct: expression of the cloned D2A and D2B subtypes in a heterologous cell line. Mol. Endocrinol. 6, 920–926 (1992).

    CAS  PubMed  Google Scholar 

  26. Senogles, S. E. The D2 dopamine receptor isoforms signal through distinct Gi alpha proteins to inhibit adenylyl cyclase. A study with site-directed mutant Gi alpha proteins. J. Biol. Chem. 269, 23120–23127 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Peverelli, E. et al. The dopamine-somatostatin chimeric compound BIM-23A760 exerts antiproliferative and cytotoxic effects in human non-functioning pituitary tumors by activating ERK1/2 and p38 pathways. Cancer Lett. 288, 170–176 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Mangili, F. et al. β-arrestin 2 is required for dopamine receptor type 2 inhibitory effects on AKT phosphorylation and cell proliferation in pituitary tumors. Neuroendocrinology 111, 568–579 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Peverelli, E. et al. Dopamine receptor type 2 (DRD2) inhibits migration and invasion of human tumorous pituitary cells through ROCK-mediated cofilin inactivation. Cancer Lett. 381, 279–286 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Casarini, A. P. et al. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 12, 297–303 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Gatto, F. et al. β-Arrestin 1 and 2 and G protein-coupled receptor kinase 2 expression in pituitary adenomas: role in the regulation of response to somatostatin analogue treatment in patients with acromegaly. Endocrinology 154, 4715–4725 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Venegas-Moreno, E. et al. Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly. J. Cell. Mol. Med. 22, 1640–1649 (2018).

    Article  CAS  PubMed  Google Scholar 

  33. Puig-Domingo, M. et al. Molecular profiling for acromegaly treatment: a validation study. Endocr. Relat. Cancer 27, 375–389 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Casar-Borota, O. et al. Expression of SST2a, but not of SSTs 1, 3, or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide. J. Clin. Endocrinol. Metab. 98, E1730–E1739 (2013).

    Article  CAS  PubMed  Google Scholar 

  35. Plöckinger, U. et al. Selective loss of somatostatin receptor 2 in octreotide-resistant growth hormone-secreting adenomas. J. Clin. Endocrinol. Metab. 93, 1203–1210 (2008).

    Article  PubMed  CAS  Google Scholar 

  36. Ferone, D. et al. Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. J. Clin. Endocrinol. Metab. 93, 1412–1417 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Wildemberg, L. E. et al. Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs. J. Endocrinol. Invest. 36, 38–43 (2013).

    CAS  PubMed  Google Scholar 

  38. Liu, W. et al. Expression of somatostatin receptor 2 in somatotropinoma correlated with the short-term efficacy of somatostatin analogues. Int. J. Endocrinol. 2017, 9606985 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Muhammad, A. et al. Pasireotide responsiveness in acromegaly is mainly driven by somatostatin receptor subtype 2 expression. J. Clin. Endocrinol. Metab. 104, 915–924 (2019).

    Article  PubMed  Google Scholar 

  40. Corbetta, S. et al. Somatostatin receptor subtype 2 and 5 in human GH-secreting pituitary adenomas: analysis of gene sequence and mRNA expression. Eur. J. Clin. Invest. 31, 208–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Ibáñez-Costa, A. et al. Octreotide and pasireotide (dis) similarly inhibit pituitary tumor cells in vitro. J. Endocrinol. 231, 135–145 (2016).

    Article  PubMed  CAS  Google Scholar 

  42. Park, C. et al. Somatostatin (SRIF) receptor subtype 2 and 5 gene expression in growth hormone-secreting pituitary adenomas: the relationship with endogenous srif activity and response to octreotide. Endocr. J. 5, 227–236 (2004).

    Article  Google Scholar 

  43. Plöckinger, U., Reichel, M., Fett, U., Saeger, W. & Quabbe, H. J. Preoperative octreotide treatment of growth hormone-secreting and clinically nonfunctioning pituitary macroadenomas: effect on tumor volume and lack of correlation with immunohistochemistry and somatostatin receptor scintigraphy. J. Clin. Endocrinol. Metab. 79, 1416–1423 (1994).

    PubMed  Google Scholar 

  44. Plöckinger, U., Bäder, M., Hopfenmüller, W., Saeger, W. & Quabbe, H. J. Results of somatostatin receptor scintigraphy do not predict pituitary tumor volume- and hormone-response to ocreotide therapy and do not correlate with tumor histology. Eur. J. Endocrinol. 136, 369–376 (1997).

    Article  PubMed  Google Scholar 

  45. Takei, M. et al. Immunohistochemical detection of somatostatin receptor (SST) subtypes 2A and 5 in pituitary adenoma from acromegalic patients: good correlation with preoperative response to octreotide. Endocr. Pathol. 18, 208–216 (2007).

    Article  PubMed  Google Scholar 

  46. Iacovazzo, D. et al. Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study. Eur. J. Endocrinol. 174, 241–250 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Gatto, F. et al. In vitro head-to-head comparison between octreotide and pasireotide in GH-secreting pituitary adenomas. J. Endocrinol. Metab. 102, 2009–2018 (2017).

    Article  Google Scholar 

  48. van der Hoek, J. et al. Distinct functional properties of native somatostatin receptor subtype 5 compared with subtype 2 in the regulation of ACTH release by corticotroph tumor cells. Am. J. Physiol. Endocrinol. Metab. 289, E278–E287 (2005).

    Article  PubMed  CAS  Google Scholar 

  49. Grant, M., Collier, B. & Kumar, U. Agonist-dependent dissociation of human somatostatin receptor 2 dimers: A role in receptor trafficking. J. Biol. Chem. 279, 36179–36183 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Grant, M., Patel, R. C. & Kumar, U. The role of subtype-specific ligand binding and the C-tail domain in dimer formation of human somatostatin receptors. J. Biol. Chem. 279, 38636–38643 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Grant, M., Alturaihi, H., Jaquet, P., Collier, B. & Kumar, U. Cell growth inhibition and functioning of human somatostatin receptor type 2 are modulated by receptor heterodimerization. Mol. Endocrinol. 22, 2278–2292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154–157 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Pellegrini, I. et al. Resistance to bromocriptine in prolactinomas. J. Clin. Endocrinol. Metab. 69, 500–509 (1989).

    Article  CAS  PubMed  Google Scholar 

  54. Caccavelli, L. et al. Decreased expression of the two D2 dopamine receptor isoforms in bromocriptine-resistant prolactinomas. Neuroendocrinology 60, 314–322 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Passos, V. Q., Fortes, M. A. H. Z., Giannella-Neto, D. & Bronstein, M. D. Genes differentially expressed in prolactinomas responsive and resistant to dopamine agonists. Neuroendocrinology 89, 163–170 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Fusco, A. et al. Somatostatinergic ligands in dopamine-sensitive and -resistant prolactinomas. Eur. J. Endocrinol. 158, 595–603 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Peverelli, E. et al. Filamin-A is essential for dopamine d2 receptor expression and signaling in tumorous lactotrophs. J. Clin. Endocrinol. Metab. 97, 967–977 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Wu, Z. B. et al. Expression of D2RmRNA isoforms and ERmRNA isoforms in prolactinomas: correlation with the response to bromocriptine and with tumor biological behavior. J. Neurooncol. 99, 25–32 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Shimazu, S. et al. Resistance to dopamine agonists in prolactinoma is correlated with reduction of dopamine D2 receptor long isoform mRNA levels. Eur. J. Endocrinol. 166, 383–390 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Ferone, D. et al. Preclinical and clinical experiences with the role of dopamine receptors in the treatment of pituitary adenomas. Eur. J. Endocrinol. 156 (Suppl. 1), S37–S43 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Saveanu, A. et al. Somatostatin and dopamine-somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas. Neuroendocrinology 83, 258–263 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Neto, L. V. et al. Expression analysis of dopamine receptor subtypes in normal human pituitaries, nonfunctioning pituitary adenomas and somatotropinomas, and the association between dopamine and somatostatin receptors with clinical response to octreotide-LAR in acromegaly. J. Clin. Endocrinol. Metab. 94, 1931–1937 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Colao, A. et al. Medical therapy for clinically non-functioning pituitary adenomas. Endocr. Relat. Cancer 15, 905–915 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Greenman, Y. et al. Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists. Eur. J. Endocrinol. 175, 63–72 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Pivonello, R. et al. Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment. J. Clin. Endocrinol. Metab. 89, 1674–1683 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Pivonello, R. et al. Dopamine receptor expression and function in corticotroph pituitary tumors. J. Clin. Endocrinol. Metab. 89, 2452–2462 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. van der Pas, R. et al. Preoperative normalization of cortisol levels in Cushing’s disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists. J. Clin. Endocrinol. Metab. 98, E1880–E1890 (2013).

    Article  PubMed  CAS  Google Scholar 

  68. Zatelli, M. C. et al. Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro. J. Mol. Endocrinol. 35, 333–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Florio, T. et al. Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study. Endocr. Relat. Cancer 15, 583–596 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Tulipano, G. et al. Differential beta-arrestin trafficking and endosomal sorting of somatostatin receptor subtypes. J. Biol. Chem. 279, 21374–21382 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Peverelli, E. et al. The third intracellular loop of the human somatostatin receptor 5 is crucial for arrestin binding and receptor internalization after somatostatin stimulation. Mol. Endocrinol. 22, 676–688 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim, K. M. et al. Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J. Biol. Chem. 276, 37409–37414 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Treppiedi, D. et al. Single-molecule microscopy reveals dynamic FLNA interactions governing SST2 clustering and internalization. Endocrinology 159, 2953–2965 (2018).

    Article  CAS  PubMed  Google Scholar 

  74. Treppiedi, D. et al. Cytoskeleton protein filamin A is required for efficient somatostatin receptor type 2 internalization and recycling through Rab5 and Rab4 sorting endosomes in tumor somatotroph cells. Neuroendocrinology 110, 642–652 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Petersenn, S., Heyens, M., Lüdecke, D. K., Beil, F. U. & Schulte, H. M. Absence of somatostatin receptor type 2 A mutations and gip oncogene in pituitary somatotroph adenomas. Clin. Endocrinol. 52, 35–42 (2000).

    Article  CAS  Google Scholar 

  76. Ballarè, E. et al. Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J. Clin. Endocrinol. Metab. 86, 3809–3814 (2001).

    Article  PubMed  Google Scholar 

  77. Peverelli, E., Lania, A. G., Mantovani, G., Beck-Peccoz, P. & Spada, A. Characterization of intracellular signaling mediated by human somatostatin receptor 5: role of the DRY motif and the third intracellular loop. Endocrinology 150, 3169–3176 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Filopanti, M. et al. Loss of heterozygosity at the SS receptor type 5 locus in human GH- and TSH-secreting pituitary adenomas. J. Endocrinol. Invest. 27, 937–942 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Ciganoka, D. et al. Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly. Eur. J. Endocrinol. 165, 517–525 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Filopanti, M. et al. Analysis of somatostatin receptors 2 and 5 polymorphisms in patients with acromegaly. J. Clin. Endocrinol. Metab. 90, 4824–4828 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Durán-Prado, M. et al. Identification and characterization of two novel truncated but functional isoforms of the somatostatin receptor subtype 5 differentially present in pituitary tumors. J. Clin. Endocrinol. Metab. 94, 2634–2643 (2009).

    Article  PubMed  CAS  Google Scholar 

  82. Luque, R. M. et al. Truncated somatostatin receptor variant SST5TMD4 confers aggressive features (proliferation, invasion and reduced octreotide response) to somatotropinomas. Cancer Lett. 359, 299–306 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Marina, D. et al. Truncated somatostatin receptor 5 may modulate therapy response to somatostatin analogues–observations in two patients with acromegaly and severe headache. Growth Horm. IGF Res. 25, 262–267 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Durán-Prado, M. et al. Truncated variants of pig somatostatin receptor subtype 5 (SST5) act as dominant-negative modulators for SST2-mediated signaling. Am. J. Physiol. Endocrinol. Metab. 303, E1325–E1334 (2012).

    Article  PubMed  CAS  Google Scholar 

  85. Friedman, E. et al. Normal structural dopamine type 2 receptor gene in prolactin-secreting and other pituitary tumors. J. Clin. Endocrinol. Metab. 78, 568–574 (1994).

    CAS  PubMed  Google Scholar 

  86. Gao, H. et al. Lower PRDM2 expression is associated with dopamine-agonist resistance and tumor recurrence in prolactinomas. BMC Cancer 15, 272 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Bueno, C., Trarbach, E. B., Bronstein, M. D. & Glezer, A. Cabergoline and prolactinomas: lack of association between DRD2 polymorphisms and response to treatment. Pituitary 20, 295–300 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Filopanti, M. et al. Dopamine D2 receptor gene polymorphisms and response to cabergoline therapy in patients with prolactin-secreting pituitary adenomas. Pharmacogenomics J. 8, 357–363 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Vallar, L., Spada, A. & Giannattasio, G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 330, 566–568 (1987).

    Article  CAS  PubMed  Google Scholar 

  90. Spada, A. et al. Clinical, biochemical and morphological correlates in patients bearing growth hormone secreting tumors with or without constitutively active adenylyl cyclase. J. Clin. Endocrinol. Metab. 71, 1421–1426 (1990).

    Article  CAS  PubMed  Google Scholar 

  91. Adams, E. F. et al. Clinical and biochemical characteristics of acromegalic patients harboring gsp-positive and gsp-negative pituitary tumors. Neurosurgery 33, 198–203 (1993).

    Article  CAS  PubMed  Google Scholar 

  92. Barlier, A. et al. Pronostic and therapeutic consequences of Gsa mutations in somatotroph adenomas. J. Clin. Endocr. Metab. 83, 1604–1610 (1998).

    CAS  PubMed  Google Scholar 

  93. Barlier, A. et al. Impact of gsp oncogene on the expression of genes coding for Gsa, Pit-1, Gi2a, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity. J. Clin. Endocr. Metab. 84, 2759–2765 (1999).

    CAS  PubMed  Google Scholar 

  94. Picard, C. et al. Gs alpha overexpression and loss of Gs alpha imprinting in human somatotroph adenomas: association with tumor size and response to pharmacologic treatment. Int. J. Cancer 121, 1245–1252 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Caccavelli, L., Morange-Ramos, I., Kordon, C., Jaquet, P. & Enjalbert, A. Alteration of G alpha subunits mRNA levels in bromocriptine resistant prolactinomas. J. Neuroendocrinol. 8, 737–746 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Ballaré, E., Mantovani, S., Bassetti, M., Lania, A. & Spada, A. Immunodetection of G proteins in human pituitary adenomas: evidence for a low expression of proteins of the Gi subfamily. Eur. J. Endocrinol. 137, 482–489 (1997).

    Article  PubMed  Google Scholar 

  97. Ritvonen, E. et al. Impact of AIP and inhibitory G protein alpha 2 proteins on clinical features of sporadic GH-secreting pituitary adenomas. Eur. J. Endocrinol. 176, 243–252 (2017).

    Article  CAS  PubMed  Google Scholar 

  98. Trivellin, G. & Korbonits, M. AIP and its interacting partners. J. Endocrinol. 210, 137–155 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Chahal, H. S., Chapple, J. P., Frohman, L. A., Grossman, A. B. & Korbonits, M. Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA). Trends Endocrinol. Metab. 21, 419–427 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Beckers, A., Aaltonen, L. A., Daly, A. F. & Karhu, A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr. Rev. 34, 239–277 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Caimari, F. & Korbonits, M. Novel genetic causes of pituitary adenomas. Clin. Cancer Res. 22, 5030–5042 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Cazabat, L. et al. Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. J. Clin. Endocrinol. Metab. 97, E663–E670 (2012).

    Article  CAS  PubMed  Google Scholar 

  103. Oriola, J. et al. Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. Eur. J. Endocrinol. 168, 9–13 (2012).

    Article  PubMed  CAS  Google Scholar 

  104. Formosa, R. & Vassallo, J. The complex biology of the aryl hydrocarbon receptor and its role in the pituitary gland. Horm. Cancer 8, 197–210 (2017).

    Article  CAS  PubMed  Google Scholar 

  105. Hernández-Ramírez, L. C. et al. Rapid proteasomal degradation of mutant proteins is the primary mechanism leading to tumorigenesis in patients with missense AIP mutations. J. Clin. Endocrinol. Metab. 101, 3144–3154 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Daly, A. F. et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. Clin. Endocrinol. Metab. 95, E373–E383 (2010).

    Article  Google Scholar 

  107. Leontiou, C. A. et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J. Clin. Endocrinol. Metab. 93, 2390–2401 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Kasuki, L. et al. AIP expression in sporadic somatotropinomas is a predictor of the response to octreotide LAR therapy independent of SST2 expression. Endocr. Relat. Cancer 19, L25–L29 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Ozkaya, H. M. et al. Germline mutations of aryl hydrocarbon receptor-interacting protein (AIP) gene and somatostatin receptor 1-5 and AIP immunostaining in patients with sporadic acromegaly with poor versus good response to somatostatin analogues. Pituitary 21, 335–346 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Chahal, H. S. et al. Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway. J. Clin. Endocrinol. Metab. 97, E1411–E1420 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Jaffrain-Rea, M. L. et al. Somatostatin analogues increase AIP expression in somatotropinomas, irrespective of Gsp mutations. Endocr. Relat. Cancer 20, 753–766 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Theodoropoulou, M. et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res. 66, 1576–1582 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Theodoropoulou, M. et al. Tumor ZAC1 expression is associated with the response to somatostatin analog therapy in patients with acromegaly. Int. J. Cancer 125, 2122–2126 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Tuominen, I. et al. AIP inactivation leads to pituitary tumorigenesis through defective Gαi-cAMP signaling. Oncogene 34, 1174–1184 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Kazlauskas, A., Poellinger, L. & Pongratz, I. The immunophilin-like protein XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor. J. Biol. Chem. 275, 41317–41324 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Ferraù, F. et al. Analysis of GPR101 and AIP genes mutations in acromegaly: a multicentric study. Endocrine 54, 762–767 (2016).

    Article  PubMed  CAS  Google Scholar 

  117. Bolger, G. B. et al. cAMP-specific PDE4 phosphodiesterases and AIP in the pathogenesis of pituitary tumors. Endocr. Relat. Cancer 23, 419–431 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schernthaner-Reiter, M. H., Trivellin, G. & Stratakis, C. A. Interaction of AIP with protein kinase A (cAMP-dependent protein kinase). Hum. Mol. Genet. 27, 2604–2613 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Daly, A. F. et al. AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients. Endocr. Connect. 8, 367–377 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cambiaghi, V. et al. Identification of human somatostatin receptor 2 domains involved in internalization and signaling in QGP-1 pancreatic neuroendocrine tumor cell line. Endocrine 56, L146–L157 (2017).

    Article  CAS  Google Scholar 

  121. Gatto, F. et al. Low beta-arrestin expression correlates with the responsiveness to long-term somatostatin analog treatment in acromegaly. Eur. J. Endocrinol. 174, 651–662 (2016).

    Article  PubMed  Google Scholar 

  122. Lesche, S., Lehmann, D., Nagel, F., Schmid, H. A. & Schulz, S. Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J. Clin. Endocrinol. Metab. 94, 654–661 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Gatto, F. et al. β-arrestin expression in corticotroph tumor cells is modulated by glucocorticoids. J. Endocrinol. 245, 101–113 (2020).

    Article  CAS  PubMed  Google Scholar 

  124. Oakley, R. H., Revollo, J. & Cidlowski, J. A. Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors. Proc. Natl Acad. Sci. USA 109, 17591–17596 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Peverelli, E. et al. cAMP/PKA-induced filamin A (FLNA) phosphorylation inhibits SST2 signal transduction in GH-secreting pituitary tumor cells. Cancer Lett. 435, 101–109 (2018).

    Article  CAS  PubMed  Google Scholar 

  126. Coelho, M. C. A. et al. Clinical significance of filamin A in patients with acromegaly and its association with somatostatin and dopamine receptor profiles. Sci. Rep. 9, 1122 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Sickler, T. et al. Filamin A and DRD2 expression in corticotrophinomas. Pituitary 22, 163–169 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Pentikäinen, U. et al. Assembly of a filamin four-domain fragment and the influence of splicing variant-1 on the structure. J. Biol. Chem. 286, 26921–26930 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Mendonsa, A. M., Na, T. Y. & Gumbiner, B. M. E-cadherin in contact inhibition and cancer. Oncogene 37, 4769–4780 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Fougner, S. L. et al. The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response. J. Clin. Endocrinol. Metab. 95, 2334–2342 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. Venegas-Moreno, E. et al. E-cadherin expression is associated with somatostatin analogue response in acromegaly. J. Cell. Mol. Med. 23, 3088–3096 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Fougner, S. L., Casar-Borota, O., Heck, A., Berg, J. P. & Bollerslev, J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin. Endocrinol. 76, 96–102 (2012).

    Article  CAS  Google Scholar 

  133. Kiseljak-Vassiliades, K. et al. Differential somatostatin receptor (SSTR) 1-5 expression and downstream effectors in histologic subtypes of growth hormone pituitary tumors. Mol. Cell. Endocrinol. 417, 73–83 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Qian, Z. R. et al. Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas. Mod. Pathol. 20, 1269–1277 (2007).

    Article  CAS  PubMed  Google Scholar 

  135. Reincke, M. et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat. Genet. 47, 31–38 (2015).

    Article  CAS  PubMed  Google Scholar 

  136. Sbiera, S. et al. The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight. Cancers 11, 1761 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  137. Albani, A. et al. The USP8 mutational status may predict long-term remission in patients with Cushing’s disease. Clin. Endocrinol. https://doi.org/10.1111/cen.13802 (2018).

    Article  Google Scholar 

  138. Losa, M. et al. Clinical characteristics and surgical outcome in USP8-mutated human adrenocorticotropic hormone-secreting pituitary adenomas. Endocrine 63, 240–246 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. Hayashi, K. et al. The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. Eur. J. Endocrinol. 174, 213–226 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Weigand, I. et al. Impact of USP8 gene mutations on protein deregulation in Cushing disease. J. Clin. Endocrinol. Metab. 104, 2535–2546 (2019).

    Article  PubMed  Google Scholar 

  141. Castellnou, S. et al. SST5 expression and USP8 mutation in functioning and silent corticotroph pituitary tumors. Endocr. Connect. 9, 243–253 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  142. D’Angelo, D. et al. Altered microRNA expression profile in human pituitary GH adenomas: down-regulation of miRNA targeting HMGA1, HMGA2, and E2F1. J. Clin. Endocrinol. Metab. 97, E1128–E1138 (2012).

    Article  PubMed  CAS  Google Scholar 

  143. Palumbo, T. et al. Functional screen analysis reveals miR-26b and miR-128 as central regulators of pituitary somatomammotrophic tumor growth through activation of the PTEN-AKT pathway. Oncogene 32, 1651–1659 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Dénes, J. et al. Regulation of aryl hydrocarbon receptor interacting protein (AIP) protein expression by MiR-34a in sporadic somatotropinomas. PLoS One 10, e0117107 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Wu, Z. B. et al. MicroRNA expression profile of bromocriptine-resistant prolactinomas. Mol. Cell. Endocrinol. 395, 10–18 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Amaral, F. C. et al. MicroRNAs differentially expressed in ACTH-secreting pituitary tumors. J. Clin. Endocrinol. Metab. 94, 320–323 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Bravo-Cordero, J. J., Magalhaes, M. A., Eddy, R. J., Hodgson, L. & Condeelis, J. Functions of cofilin in cell locomotion and invasion. Nat. Rev. Mol. Cell. Biol. 14, 405–415 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Meij, B. P., Lopes, M. B., Ellegala, D. B., Alden, T. D. & Laws, E. R. Jr. The long-term significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J. Neurosurg. 96, 195–208 (2002).

    Article  PubMed  Google Scholar 

  149. Losa, M. et al. Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence. J. Neurosurg. 108, 525–532 (2008).

    Article  PubMed  Google Scholar 

  150. Molitch, M. E. Pharmacologic resistance in prolactinoma patients. Pituitary 8, 43–52 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. University of Milan, Department of Clinical Sciences and Community Health, Milan, Italy

    Erika Peverelli, Donatella Treppiedi, Federica Mangili, Rosa Catalano, Anna Spada & Giovanna Mantovani

  2. PhD Program in Endocrinological Sciences, Sapienza University of Rome, Rome, Italy

    Rosa Catalano

  3. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy

    Giovanna Mantovani

Authors
  1. Erika Peverelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donatella Treppiedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Federica Mangili
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosa Catalano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Spada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giovanna Mantovani
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Erika Peverelli.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks the anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-021-00514-0

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer