Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment.
Introduction of somatostatin analogs has greatly contributed to improving the prognosis of acromegaly. Although the majority of patients are effectively treated by these agents, resistance occurs in a subset of patients. So far, resistance to somatostatin has never been associated with mutations of the somatostatin receptor subtypes (sst2 and sst5) that inhibit GH secretion. Molecular analysis of genomic DNA from pituitary tumor and peripheral blood obtained from an acromegalic resistant to octreotide showed a somatic activating mutation of Gsalpha (Arg201Cys), no mutation in sst2, and one polymorphism (Pro109Ser) and one germ line mutation (Arg240Trp) in sst5. Wild-type (WT) and mutant sst5 PCR products were cloned and transfected into Chinese hamster ovary K1 cells. In Chinese hamster ovary K1 cells stably expressing mutant sst5, somatostatin-28 was less potent in inhibiting cyclic AMP levels than in WT cells. Proliferation of mutant cells exceeded that of WT by 50%. Moreover, somatostatin reduced cell growth and MAPK activity in WT but not in mutant cells in which the peptide even increased MAPK activity. We suggest that this mutation that abrogates the antiproliferative action of somatostatin and activates mitogenic pathways may be involved in the resistance to somatostatin treatment.
Ballarè
E
E
Institute of Endocrine Sciences, University of Milano 20122, Ospedale Maggiore IRCCS, 20122 Milan, Italy.
Persani
L
L
Lania
A G
AG
Filopanti
M
M
Giammona
E
E
Corbetta
S
S
Mantovani
S
S
Arosio
M
M
Beck-Peccoz
P
P
Faglia
G
G
Spada
A
A
D000172:Acromegaly / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics*; D000236:Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D019943:Amino Acid Substitution; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004351:Drug Resistance; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015282:Octreotide / Q000494:pharmacology / Q000627:therapeutic use*; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; D017481:Receptors, Somatostatin; D011994:Recombinant Proteins; C094573:somatostatin receptor 5; C093733:somatostatin receptor 2; D020928:Mitogen-Activated Protein Kinases; D015282:Octreotide