Combination of rapamycin and somatostatin analogues for the treatment of nonfunctioning pituitary tumors

The purpose of this study is to analyze and reverse the resistance to the antiproliferative action of somatostatin analogues in nonfunctioning pituitary adenomas. We have previously shown that the somatostatin analogue octreotide decrease cell growth by blocking components of the PI3K/Akt pathway. To search whether overactivation of this pathway may be responsible for the somatostatin analogue resistance, immortalized pituitary tumor cells lines, which are known to respond to this kind of treatment by decreasing cell proliferation, were transfected with an Akt overexpressing vector and cell growth was determined by thymidine incorporation and a non-radioactive colorimetric assay. Akt overexpression rendered these cells unresponsive to octreotide antiproliferative treatment, indicating a role for Akt in somatostatin analogue resistance. To investigate combination therapies that could allow tumors to benefit from this treatment, pituitary tumors (n=26) were cultured and treated with octreotide and with the mTOR inhibitor rapamycin alone or in combination. Treatment with rapamycin decreased cell proliferation in immortalized pituitary tumor cells by 50%, but had low efficiency in pituitary tumors in primary cell culture (13%±17). Addition of octreotide to rapamycin treatment decreased cell viability in all 26 tumors examined (40%±13), while octreotide alone had little effect (12%±9). Western blot analysis of immortalized pituitary tumor cell lysates revealed that the rapamycin mediated increase in Akt phosphorylation was blocked by octreotide co-treatment, while reduction in p70 S6K phosphorylation was evident after individual and combined rapamycin and octreotide treatment. Summarizing, these data show that combining somatostatin analogues with mTOR inhibitors may be more effective to reduce growth than either substance alone. This strategy can be useful not only to overcome resistance to somatostatin analogue treatment in nonfunctioning pituitary adenomas.