Targets for Gastrointestinal Stromal Tumor

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with pathogenesis strongly driven by aberrant activation of specific receptor tyrosine kinases and their downstream signaling pathways. The most critical molecular targets in GIST pathobiology are KIT proto-oncogene (KIT) and platelet-derived growth factor receptor alpha (PDGFRA), both of which harbor activating mutations in the majority of GIST cases. These mutations lead to constitutive kinase activation, uncontrolled cell proliferation, and tumorigenesis. Additional targets, such as ATP-binding cassette transporters (ABCB1 and ABCG2), contribute to drug resistance mechanisms, while heat shock proteins (HSP90AA1 and HSP90AB1) act as molecular chaperones stabilizing mutant kinases. ABL1, though not mutated in GIST, is involved in downstream signaling and is a secondary target of some kinase inhibitors. The mechanistic understanding of these targets has enabled the development of targeted therapies, most notably tyrosine kinase inhibitors (e.g., imatinib, sunitinib). Categorizing these targets by their direct involvement in oncogenic signaling, resistance mechanisms, and chaperone function provides a strategic framework for therapeutic intervention and drug development in GIST. Only targets with well-established, direct roles in GIST pathogenesis or treatment resistance are included in the following analysis.

Oncogenic Receptor Tyrosine Kinases

This category comprises receptor tyrosine kinases that are directly implicated in the pathogenesis of GIST through activating mutations or overexpression. The most prominent are KIT proto-oncogene (KIT) and platelet-derived growth factor receptor alpha (PDGFRA). These kinases are central drivers of GIST tumorigenesis, with mutations leading to constitutive activation of proliferative and anti-apoptotic signaling pathways. Their pivotal role in disease onset and progression makes them the primary therapeutic targets in GIST.

KIT proto-oncogene, receptor tyrosine kinase (KIT)

KIT proto-oncogene, receptor tyrosine kinase (KIT) is a type III receptor tyrosine kinase characterized by an extracellular immunoglobulin-like domain, a transmembrane region, and an intracellular split tyrosine kinase domain. Mutations in KIT, particularly in exons 9, 11, 13, and 17, result in constitutive activation independent of ligand binding, driving GIST pathogenesis. KIT signaling activates downstream MAPK, PI3K/AKT, and JAK/STAT pathways, promoting proliferation and survival. KIT mutations are found in approximately 75-80% of GIST cases, and their presence is both diagnostic and prognostic. KIT is the primary molecular target of imatinib and other TKIs, which inhibit its kinase activity and induce tumor regression. KIT status is used as a predictive biomarker for therapy response. (Entrez: 3815; KEGG: 3815; UniProt: P10721, A0A8I5KS03)

Platelet derived growth factor receptor alpha (PDGFRA)

Platelet derived growth factor receptor alpha (PDGFRA) is a type III receptor tyrosine kinase structurally related to KIT, with a similar domain organization. Activating mutations, most commonly in exon 18 (D842V), are present in 5-10% of GISTs, leading to ligand-independent activation of downstream signaling cascades such as MAPK and PI3K/AKT. PDGFRA-mutant GISTs are clinically distinct, often occurring in the stomach and showing different responses to TKIs; for example, the D842V mutation confers resistance to imatinib but sensitivity to avapritinib. PDGFRA mutation status is essential for therapeutic decision-making and risk stratification. (Entrez: 5156; KEGG: 5156; UniProt: P16234)

Drug Resistance Mechanisms

This category includes ATP-binding cassette (ABC) transporters that mediate multidrug resistance by actively effluxing tyrosine kinase inhibitors out of GIST cells, thereby reducing drug efficacy. ABCB1 (P-glycoprotein) and ABCG2 (BCRP) are the principal transporters implicated in acquired resistance to imatinib and other TKIs. Their upregulation is associated with treatment failure and disease progression.

ATP binding cassette subfamily B member 1 (ABCB1)

ATP binding cassette subfamily B member 1 (ABCB1), also known as P-glycoprotein, is a transmembrane transporter with two nucleotide-binding domains and two transmembrane domains. It utilizes ATP hydrolysis to export a wide range of substrates, including chemotherapeutic agents and TKIs, out of cells. Overexpression of ABCB1 in GIST leads to reduced intracellular concentrations of imatinib and other drugs, contributing to acquired resistance. Inhibition of ABCB1 has been shown to restore drug sensitivity in preclinical models, and its expression is associated with poor prognosis. (Entrez: 5243; KEGG: 5243; UniProt: P08183)

ATP binding cassette subfamily G member 2 (ABCG2)

ATP binding cassette subfamily G member 2 (ABCG2), also known as breast cancer resistance protein (BCRP), is a half-transporter that forms homodimers to function. Like ABCB1, ABCG2 actively effluxes TKIs, including imatinib and sunitinib, out of GIST cells. Increased expression of ABCG2 has been correlated with resistance to therapy and disease recurrence. Pharmacological inhibition of ABCG2 can enhance drug retention and efficacy. (Entrez: 9429; KEGG: 9429; UniProt: Q9UNQ0)

Chaperone-Mediated Kinase Stabilization

This category encompasses molecular chaperones, specifically heat shock proteins HSP90AA1 and HSP90AB1, which are essential for the stability and function of mutant KIT and PDGFRA proteins. By stabilizing these oncoproteins, HSP90 facilitates their oncogenic signaling and contributes to GIST cell survival. Targeting HSP90 disrupts this chaperone-client interaction, leading to degradation of mutant kinases and tumor regression.

Heat shock protein 90 alpha family class A member 1 (HSP90AA1)

Heat shock protein 90 alpha family class A member 1 (HSP90AA1) is a cytosolic molecular chaperone with an N-terminal ATPase domain, middle domain, and C-terminal dimerization domain. HSP90AA1 binds and stabilizes mutant KIT and PDGFRA, preventing their proteasomal degradation. Inhibition of HSP90 leads to destabilization and degradation of these kinases, resulting in decreased signaling and tumor cell death. HSP90 inhibitors, such as ganetespib, have demonstrated preclinical efficacy in GIST models. (Entrez: 3320; KEGG: 3320; UniProt: P07900)

Heat shock protein 90 alpha family class B member 1 (HSP90AB1)

Heat shock protein 90 alpha family class B member 1 (HSP90AB1) is another cytosolic HSP90 isoform, structurally similar to HSP90AA1, with a key role in stabilizing mutant kinases in GIST. It forms complexes with HSP90AA1 and co-chaperones, maintaining the active conformation of KIT and PDGFRA. Inhibition of HSP90AB1, together with HSP90AA1, disrupts oncoprotein stability and is a promising therapeutic strategy. (Entrez: 3326; KEGG: 3326; UniProt: P08238)

Non-Receptor Tyrosine Kinase Signaling

This category includes non-receptor tyrosine kinase ABL1, which, while not mutated in GIST, is a secondary target of imatinib and may contribute to downstream signaling cascades activated by KIT and PDGFRA. Its inhibition may have ancillary effects on tumor cell signaling and survival.

ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1)

ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) is a cytoplasmic and nuclear kinase with SH3, SH2, and tyrosine kinase domains. Although not directly mutated in GIST, ABL1 is a pharmacological target of imatinib, which was originally developed as an ABL inhibitor. ABL1 may participate in downstream signaling from activated KIT/PDGFRA, influencing cell proliferation and survival. Its inhibition may contribute to the antitumor activity of TKIs in GIST. (Entrez: 25; KEGG: 25; UniProt: P00519)