New treatment strategies for advanced-stage gastrointestinal stromal tumours

Abstract

When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.

Fig. 1 │. Summary of GIST molecular subtypes.

The pie chart indicates the proportion of gastrointestinal stromal tumour (GIST) cases that is driven by each recurrent driver alteration associated with this disease. KIT and PDGFRA mutations account for approximately 85% of GISTs. Effective targeted therapies are now available for patients with GIST harbouring such alterations, as well as those with BRAF mutations or receptor tyrosine kinase gene fusions (predominantly involving FGFR1 or NTRK3), encompassing ~88% of all advanced-stage GISTs (indicated by the black segment of the outer ring). The remaining 12% of GISTs are SDH deficient, NF1, PIK3CA or RAS mutant, or otherwise wild type, and lack effective therapies (indicated by the blue segment of the outer ring).

Fig. 2 │. GIST signalling pathways, drug targets and current systemic therapies.

a │ The genetic alterations that drive gastrointestinal stromal tumours (GISTs) generally result in activation of signalling through the MEK–ERK (MAPK), JAK–STAT and PI3K–AKT pathways to prevent apoptosis and drive cell survival and proliferation. The components of these pathways and upstream receptor tyrosine kinases that are recurrently mutated in GIST are shown in red ovals and boxes, respectively; those indicated with an asterisk can also arise as secondary mutations after therapy. Gain-of-function (activating) mutations are found in positive signalling effectors, including KIT, PDGFRA, fusion proteins involving NTRK3 (TRKC) or FGFR1, as well as RAS, PI3Kα or BRAF. Loss-of-function (inactivating) mutations are found in tumour suppressors, such as neurofibromatosis-related protein NF1 (also known as neurofibromin). b │ GIST can also be driven by deficiency of the mitochondrial respiratory complex II, succinate dehydrogenase (SDH), resulting from a genetic mutation in any one of the four SDH subunit genes (SDHA, SDHB, SDHC or SDHD), or more rarely from epigenetic inactivation of SHDC via promoter hypermethylation. Inactivation of the SDH complex results in an accumulation of succinate, which leads to competitive inhibition of α-ketoglutarate-dependent dioxygenases, including those of the hypoxia-inducible factor (HIF)-prolyl hydroxylase domain (PHD), ten-eleven translocation methylcytosine dioxygenase (TET), and lysine-specific histone demethylase (KDM) families. In turn, inhibition of PHDs leads to pseudohypoxia by preventing von Hippel-Lindau disease tumour suppressor (pVHL)-mediated ubiquitination and subsequent proteasomal degradation of HIF, while inhibition of TET and KDM proteins results in increased methylation of DNA and histones, respectively, and thus broad epigenetic reprogramming. Ub, ubiquitin.

Fig. 3 │. Typical pattern of GIST response and evolution during TKI treatment.

Patients diagnosed with metastatic KIT-mutant gastrointestinal stromal tumour (GIST; lesions indicated by grey cells) are initially treated with the KIT-targeting tyrosine kinase inhibitor (TKI) imatinib. Typically, imatinib induces tumour shrinkage by inducing apoptosis of GIST cells; however, not all GIST cells are eradicated, with a fraction persisting throughout treatment by entering a non-proliferative, quiescent state (imatinib-persistent GIST cells, shown in blue). Some of these persistent GIST cells will eventually acquire genetic mutations that confer resistance to imatinib, leading to tumour outgrowth and disease progression (pink and purple cells). Other KIT TKIs can be administered sequentially to patients with GISTs harbouring resistance mutations. Nevertheless, genetically heterogeneous subclones can arise across tumour lesions (shown as pink, purple and red cells), leading to polyclonal resistance of the tumours to multiple TKIs. Both intertumour and intratumour heterogeneity can be found in patients with TKI-resistant GIST. Intertumour heterogeneity is illustrated by the presence of different imatinib-resistant subclones, either pink or purple, across the two lesions. In the rightmost panel, intratumour heterogeneity is also depicted by the co-existence within a single lesion of newly emergent red subclones together with the pink or purple cell population.

Fig. 4 │. New therapeutic approaches exploiting different elements of GIST biology.

a │ Tyrosine kinase inhibitor (TKI)-based therapy remains relevant for the majority of patients with advanced-stage GIST, particularly those with KIT-mutant disease; however, new strategies are required to overcome treatment resistance and thereby improve outcomes, including the development of more-potent TKIs, or combinations of two TKIs or a TKI plus inhibitors of downstream effector kinases (such as MEK and/or PI3K). Many of these approaches might also be applicable in PDGFRA-mutant GIST if PDGFRA-specific TKIs, such as avapritinib, are utilized. b │ The antibody–drug conjugate (ADC) DS-6157a combines an anti-G protein-coupled receptor 20 (GPR20) antibody and the DNA topoisomerase I (TOPO1) inhibitor deruxtecan (Dxd). Upon binding to GPR20, the receptor–ADC complex is endocytosed, with subsequent lysosomal degradation of the complex resulting in release of the Dxd payload that in turn causes DNA damage and cell death. c │ ¹⁷⁷Lu-NeoB is a radioligand therapy (RLT) consisting of the radioisotope ¹⁷⁷Lu conjugated via the chelating agent dodecanetetraacetic acid (DOTA) to a peptide antagonist of the gastrin-releasing peptide receptor (GRPR; also known as bombesin receptor subtype 2 (BB₂)). Thus, this agent enables specific intracellular delivery of radiation to GRPR-expressing GIST cells, resulting in DNA damage and apoptosis. d │ In an approach specific to SDH-deficient GIST cells, treatment with the alkylating agent temozolomide (TMZ) can cause irreparable DNA damage and cell death. This vulnerability is probably at least partially attributable to epigenetic silencing of 6-O-methylguanine-DNA methyltransferase (MGMT), which is involved in the repair of alkylated DNA, as a consequence of the metabolic alterations resulting from SDH deficiency in these cells. e │ Various immuno-oncology approaches to the treatment of GIST have been proposed, including combining a TKI with PD-1 and/or CTLA4 immune-checkpoint inhibitors to simultaneously suppress GIST cells while stimulating antitumour T cells, or imatinib with an immunostimulant such as IFNα to prevent imatinib-related T cell inactivation.