Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.
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机译：各种分子触发因素定义了胃肠道间质瘤（GIST）的异质子集，其临床行为和药物敏感性不同。 KIT / PDGFRA野生型GIST（包括那些琥珀酸脱氢酶（SDH）缺陷）总体上对常用的酪氨酸激酶抑制剂无反应，从而促进了特定替代治疗策略的发展。 O 6 -甲基鸟嘌呤-DNA甲基转移酶（MGMT）通过启动子甲基化的表观遗传失活导致烷基化剂在几种人类癌症中的有效性。 SDH缺陷型GIST通常具有广泛的DNA甲基化特征。然而，迄今为止尚未研究过这些肿瘤中MGMT甲基化的实际发生，可能使它们对烷基化药物有反应。在这里，我们讨论了有关在不同GIST亚组（包括SDH缺陷型）中发生MGMT甲基化的最新发现，作为可能重新评估专门针对这些较小的，否则是整体化学难治性GIST亚组的烷基化剂的前提。
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