Advances in therapy of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) comprise a heterogeneous group of the most common mesenchymal neoplasms of the gastrointestinal tract. The majority of GISTs are associated with activating, somatic, mutually exclusive mutations of two genes, KIT and PDGFRA (platelet-derived growth factor receptor-alpha), which are the early oncogenic events during GIST development (1). However, approximately 10–15% of GISTs lack oncogenic KIT or PDGFRA mutations and these tumors are often called “wild type” (WT) GISTs. They are indistinguishable from KIT/PDGFRA-mutated tumors in terms of morphology, anatomic localization and the expression of two diagnostic markers, i.e., KIT and DOG-1. Yet, they are a very heterogeneous group of tumors from the molecular point of view, which based on their succinate dehydrogenase (SDH) immunohistochemical status can be classified into two main subtypes, i.e., SDH-competent and SDH-deficient tumors. The former constitute mainly GIST related to neurofibromatosis type 1 (von Recklinghausen disease), but include also rare tumors that carry BRAF exon 15 mutations, oncogenic fusions of neurotrophic tyrosine kinase (NTRK), fusions or mutations in fibroblast growth factor receptor (FGFR) genes, and tumors of yet unknown driver mechanisms (2,3). In some of these WT cases (especially pediatric) overexpression of insulin-like growth factor 1 receptor (IGF1R) has been observed (4). The SDH-deficient GISTs form a distinctive subset of tumors, which results from the loss of function mutations in the genes encoding the SDH enzyme complex. These tumors comprise the majority of pediatric GISTs, low percentage of sporadic cases, and two classes of syndromic GISTs (Carney triad and Carney-Stratakis syndrome) (5-8). They are characterized by predominant location in the stomach, multifocality and often indolent clinical behavior even in metastatic disease

The introduction of imatinib mesylate—a small-molecule selective inhibitor of receptor tyrosine kinase, has revolutionized the therapy of advanced (inoperable and/or metastatic) GIST (9), and subsequently imatinib was applied in adjuvant therapy after resection of high-risk GIST (10). In case of GIST progression on imatinib therapy, the commonly used strategy is to introduce alternative molecular targeted agents as sunitinib, regorafenib and ripretinib (11-13).

KIT and PDGFRA mutational status strongly correlates with the response and progression-free survival (PFS) in GIST patients treated with imatinib. In general, patients with tumors harboring KIT exon 11 mutations demonstrate the best clinical response to imatinib with the highest rate of objective responses (70–85% of patients) and the longest overall and PFS (14,15). It has been observed that WT GIST had inferior response to imatinib and other tyrosine kinase inhibitors. Specifically, the SDH-deficient tumors are not well recognized in terms of sensitivity to tyrosine kinase inhibitors in large phase II and III clinical trials. Nevertheless, it seems that SDH-mutated GISTs do not respond well to the commonly used targeted therapy, with no objective tumor response to imatinib (16). Recently, Nannini and co-workers made a comprehensive review of targeted therapy in SDH-deficient GIST (17). Authors highlighted that disturbances in SDH complex lead to activation of hypoxia-inducible factor (HIF), what makes rationale for antiangiogenic drugs. They presented the overview of available data on the activity of different kinase inhibitors in this GIST subtype and confirmed low efficacy of these drugs, even beyond imatinib, especially in terms of objective responses. Authors underlined also that interpretation of disease stabilization in SDH-deficient GISTs is difficult in interpretation due to indolent course of disease. Nevertheless, our multicenter series of pediatric/young adult patients with advanced KIT/PDGFRA WT GISTs treated with sunitinib (strong antiangiogenic inhibitor), confirmed some clinical benefits of sunitinib in this population (18). These data were similar to series of Janeway et al. in pediatric GISTs patients, in which longer time to progression on sunitinib as compared to prior imatinib therapy was observed (19).

Very interesting molecular data indicate that O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is markedly prevalent in SDH-deficient GISTs, what may imply sensitivity to alkylating agents. With this regard, Nannini et al. did not mention in this review the results of preclinical and clinical data presented by Yebra et al. during 2019 Annual Meeting of Connective Tissue Oncology Society, which demonstrated therapeutic vulnerability of SDH-deficient GISTs to DNA alkylating agent, temozolomide, and 40% rate of objective responses among five patients treated with this drug (20,21). Phase II study (NCT03556384) is ongoing. Further preclinical and clinical research on SDH-deficient GISTs is needed.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gastrointestinal Stromal Tumor. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-22-6/coif). PR received payment or honoraria from BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi and he is on the Advisory Board of MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Medicines and Philogen. MDR has no conflicts of interests to declare.

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