{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:45:24Z","timestamp":1792111524355,"version":"4.4.0"},"reference-count":51,"publisher":"The Endocrine Society","issue":"11","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Temozolomide (TMZ) can be an effective medical treatment for aggressive pituitary tumors. In case of disease recurrence following TMZ treatment, however, treatment with the drug generally does not control tumor regrowth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This work aimed to better understand the mechanisms of resistance of corticotroph tumors to TMZ in the context of heterogeneity of methylguanine-DNA methyltransferase (MGMT) expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed immunohistochemical analysis of the MGMT expression pattern in 25 corticotroph tumors to evaluate intratumoral heterogeneity. In addition, we created in vitro models of AtT20 corticotroph tumor cells with acquired TMZ-resistance after exposure to high- and low-dose TMZ, the latter representing a clinically achievable TMZ level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MGMT immunostaining in corticotroph tumors showed a considerable heterogeneous intertumoral and intratumoral distribution pattern in 80% of tumors. In the in vitro model, high- and low-dose TMZ challenges induced a 6.3- and 3.4-fold decreased sensitivity to the growth inhibitory effect of TMZ. TMZ-induced changes in cell cycle phases were lower in TMZ-resistant cells than in vehicle-challenged cells. TMZ-resistant cells had higher Mgmt messenger RNA and protein expression and 1.8-fold higher number of Mgmt-positive cells. No difference was observed in the level of Mgmt promoter methylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Corticotroph pituitary tumors demonstrate a high intertumoral and intratumoral heterogeneity in MGMT expression. In an acquired TMZ-resistant corticotroph pituitary tumor cell model, TMZ resistance was associated with strong increase in MGMT expression and percentage of MGMT-positive cells. We hypothesize that clonal selection of high MGMT-expressing cells is involved in this acquired TMZ resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag170","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:03:44Z","timestamp":1778760224000},"page":"3196-3208","source":"Crossref","is-referenced-by-count":0,"title":["Heterogeneity of MGMT expression in corticotroph adenomas and mechanism of acquired temozolomide resistance"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3078-5200","authenticated-orcid":false,"given":"Ticiana","family":"Paes","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC Cancer Institute, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]},{"name":"Department of Internal Medicine, Roger Williams Medical Center , Providence, RI 02908 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2319-391X","authenticated-orcid":false,"given":"Richard A","family":"Feelders","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC Cancer Institute, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]},{"name":"Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, NewYork University Langone Medical Center , New York, NY 10016 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadime","family":"Dogan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC Cancer Institute, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand M","family":"Iyer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC Cancer Institute, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan M","family":"Kros","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Dina Recanati School of Medicine, Reichman University , Herzliyya 4610101 ,","place":["Israel"]},{"name":"Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center , Ramat Gan 52621 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M","family":"van Koetsveld","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC Cancer Institute, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4897-2197","authenticated-orcid":false,"given":"Leo J","family":"Hofland","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Erasmus MC Cancer Institute, Erasmus Medical Center , Rotterdam 3015 GD, T","place":["he Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"issue":"2","key":"2026101520021614100_dgag170-B1","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s11154-020-09551-y","article-title":"Temozolomide therapy for aggressive pituitary tumours - current understanding and future perspectives","volume":"21","author":"Burman","year":"2020","journal-title":"Rev Endocr Metab 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