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Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST

ABSTRACT: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design novel inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 newly determined co-crystal structures, including the first structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazolinebased inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure offers new insights for targeting solvent-front mutations across oncogenic kinases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Cell Culture

SUBMITTER: Nicola Berner

LAB HEAD: Bernhard Kuster

PROVIDER: PXD077574 | Pride | 2026-08-03

REPOSITORIES: Pride

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			Action	DRS
	2024-01-18-decoys-contam-uniprot-sp_canonical_160322_PFAM_v03.12.15.fasta.fas	Fasta
	7206_YA12_P109383_PD_R1.raw	Raw
	7206_YA1_P109295_PD_R1.raw	Raw
	7206_YA2_P109303_PD_R1.raw	Raw
	7206_YA3_P109311_PD_R1.raw	Raw

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GIST: Assessment of Tumor Mutations and TKI Plasma Exposure

Project description:Gastrointestinal stromal tumors (GISTs) belong to the sarcoma group and are characterized by oncogenic mutations in the c-KIT, PDGFRA, BRAF and NF-1 genes that drive tumor growth. Since tyrosine kinase inhibitors (TKIs) have become available, the median survival of GIST patients increased from 9 months to over 5 years. Consequently, this rare disease has become a role model for other targeted therapies. However, response to TKIs is extremely heterogeneous: ~15% of the patients experience no benefit from imatinib, whereas ~17% of the patients enjoy stable disease for over 9 years. Treatment failure due to primary and secondary resistance is caused in part by mutations in oncogenic genes that cause change in drug sensitivity. A new technique, using circulating tumor DNA, has enabled us to assess mutations in a simple blood sample obtained from patients on treatment, and thus detect new mutations early in the course of the disease. Also, differences in pharmacokinetic drug behavior add to the observed heterogeneity, and may cause resistance due to drug underexposure and thereby proliferation of the least sensitive tumor cells. This offers the opportunity to optimize and personalize targeted treatment for individual GIST patients by timely treatment adaptation based on early detection of secondary TKIs resistance mutations. Achieving this urgently requires data on daily clinical practice, including prospective serial mutation analysis and serial drug plasma concentration measurement. At a fundamental level this will also help to unravel the driving factors behind primary and secondary TKIs resistance in this model disease.

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Homo sapiens

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Kinome Profiling of Gastrointestinal Stromal Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies Wee1 as a Candidate Therapeutic Target

Project description:Purpose: Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical obstacle. Development of effective treatment strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Experimental Design: Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and succinate dehydrogenase-deficient GIST) to identify novel kinase targets. In vitro and in vivo studies were performed to evaluate the utility of targeting the identified kinases in GIST. Results: Kinome profiling revealed distinct signatures in three GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in both KIT and PDGFRA-mutant GIST cell lines, as well as notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. Conclusions: These studies provide strong preclinical justification for the use of MK-1775 in GIST.

2021-09-09 | PXD020720 | Pride

Transcription profiling of human gastrointestinal stromal tumours according to KIT mutations and expression

Project description:Gastrointestinal stromal tumours (GISTs) represent a heterogeneous group of tumours of mesenchymal origin characterized by gain-of-function mutations in KIT or PDGFRA of the type III receptor tyrosine kinase family. Although mutations in either receptor are thought to drive an early oncogenic event through similar pathways, two previous studies reported the mutation-specific gene expression profiles. However, their further conclusions were rather discordant. To clarify the molecular characteristics of differentially expressed genes according to GIST receptor mutations, we combined microarray-based analysis with detailed functional annotations. Experiment Overall Design: 29 samples: 15 with KIT mutation detected, 11 with PDGFRA mutation detected, 3 with no mutation detected

2009-09-05 | E-GEOD-17743 | biostudies-arrayexpress

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Project description:Tyrosine kinase inhibitor (TKIs) resistance remains the leading obstacle for treating gastrointestinal stromal tumor (GIST), in which the secondary mutations within KIT causes escape of TKI inhibition and KIT reactivation. Here we found FTO was highly expressed in GIST and positively correlated with the high-grade and recurrence liability. m6A-seq and RNA-seq analyses of GIST cells treated with FTO inhibitor CS1 demonstrated that FTO demethylated the m6A modification in the 3’UTR of KIT mRNA, which in turn partially blocked recognition by m6A reader YTHDF2, thus enhanced KIT mRNA stability. Pharmacological inhibition or genetic knockdown of FTO led to decreased KIT expression, mitigated malignant phenotypes and increased imatinib sensitivity in vitro, while genetic knockout of FTO or entacapone treatment combined with imatinib evoked regression of tumor in KIT-Asp818Tyr/+ heterozygote GIST mouse model. Phase I trial in five TKIs-refractory GIST patients with a combination of entacapone and imatinib (NCT 04006769) demonstrated that two of three assessable participants (66.7%) achieved partial remission. Our results suggest that targeting FTO is a feasible therapeutic strategy for clinical management of TKI resistance and recurrence of GIST.

2026-06-10 | GSE240411 | GEO

Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression.

2013-05-22 | GSE34387 | GEO

Oncogenic SDH mutation underlies global epigenomic instability in gastrointestinal stromal tumor

2013-05-22 | E-GEOD-34387 | biostudies-arrayexpress

Identification of common features proffered by KIT and PDGFRA mutations in gastro-intestinal stromal tumors

Project description:Mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet derived growth factor receptor alpha (PDGFRA) are responsible for more than 85% of the gastrointestinal stromal tumors (GIST). The introduction of imatinib in the therapy scheme of GIST revolutionized the patient outcome. Unfortunately, the therapy allows a disease stabilization rather than curation. Resistance to the inhibitor arises in most cases within the two first years of therapy. The identification of new targets to treat GIST is now essential. We propose a thorough investigation of the activating mechanisms derived from the main PDGFRA and KIT mutants encountered in the GIST landscape. We identified striking differences among the different KIT mutants while PDGFRA mutants delivered a very uniform picture. KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity and all KIT mutants were, in addition to their constitutive activation, responsive to stem cell factor (SCF) stimulation. This highlights the importance of evaluating the SCF expression profile in GIST patients. In contrast, PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a very high intrinsic kinase activity. At the transcriptomic level, the mitogen-activated protein kinase (MAPK) pathway was established as the most prominent activated pathway, commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway using the MEK inhibitor PD0325901 reduced the proliferation of GIST primary cells in the nanomolar range. This demonstrates the high value of MEK inhibitors for combination therapy in GIST treatment. This experiment contains expression data from HEK-293 cells expressing wild-type and mutant KIT. The mutants included in the study correspond to the main mutations found in GIST, mainly KIT Ex9 exhibits a duplication of AY502-503 and KIT Ex11 a deletion of residues 553 to 557.

2017-07-05 | E-MTAB-4548 | biostudies-arrayexpress

Constitutive activation of oncogenic PDGFR-mutants found in GIST patients induces receptor mislocalisation and alters PDGFR-A signalling characteristics

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