Targeting the IGF-IR system in pituitary tumors in vitro: antiproliferative action & pitfalls
M. Theodoropoulou1, M. Tichomirowa2, V. Cerovac1, J. Monteserin1, H. Rubinfeld3 & G. Stalla1
IGF-I receptors (IGF-IR) and their aberrant signaling cascade contribute to the pathogenesis of several solid cancers. Pituitary adenomas express IGF-IR and present with overactivation of the IGF-IR pathway. The aim of the study was to identify the potential antiproliferative action of the small molecule IGF-IR inhibitor NVP-TAE226 on acromegalic (n=11) and nonfunctioning pituitary adenomas (NFPA; n=15) in primary cell culture. Changes in cell viability were determined by thymidine incorporation and a nonradioactive colorimetric assay. The compound at the 100 nM concentration suppressed cell viability by more than 20% in 9 out of 15 NFPA (mean growth suppression as % of vehicle control: 30±15) and in 10 acromegalic tumors (29±7), while at 10 nM it was efficacious in 8 NFPA (24±10) and 4 acromegalic tumors (28±14). Inhibiting the PI3K pathway in the same tumors using BEZ235 suppressed cell viability at 10 nM concentration in all NFPA (48±20) and in two acromegalic tumors (31±15). In contrast, mTOR inhibition with everolimus was efficacious in 4 out of 15 NFPA (25±10) and in all but one acromegalic cases (48±17). Put together, these data indicate a tumor specific dependency to the different IGF-IR signaling branches, with NFPA being sensitive to PI3K inhibition and acromegalic tumors to the mTOR inhibition.
IGF-IR inhibition in acromegalic tumors in vitro was accompanied by increased GH secretion (GH normalized to cell viability assay counts; mean suppression as % of vehicle control: 46±10). Similar GH increase was observed after mTOR but not in the same extend after PI3K inhibition (42±31 vs 20±14; P=0.043), indicating a role for the mTOR pathway on GH synthesis.
Altogether, IGF-IR inhibitors have a potential as antiproliferative agents for the treatment of NFPA. In contrast their potent antiproliferative action in acromegalic tumors is compromised by the concomitant increase in GH secretion.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.