Reference Detail

Ref Type

Journal Article

PMID

(29100343)

Authors

Na YS, Ryu MH, Yoo C, Lee JK, Park JM, Lee CW, Lee SY, Shin YK, Ku JL, Ahn SM, Kang YK

Title

Establishment and characterization of patient-derived xenograft models of gastrointestinal stromal tumor resistant to standard tyrosine kinase inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	8	44	2017 Sep 29	76712-76721	Oncotarget

URL

Abstract Text

Gastrointestinal stromal tumors (GISTs) with KIT or platelet-derived growth factor receptor alpha (PDGFRa) oncogenic driver gene mutations, respond to tyrosine kinase inhibitors (TKIs) including imatinib, sunitinib, and regorafenib. However, most patients develop TKI resistance; therefore, novel agents are required. We established three TKI-resistant GIST patient-derived xenograft (PDX) models for effective drug development. These were PDX models harboring primary and secondary KIT and additional mutations; KIT exon 11 (p.Y570_L576del), KIT exon 17 (p.D816E), and PTEN (p.T321fs) mutations in GIST-RX1 from a patient who was unresponsive to imatinib, sunitinib, and sorafenib, and KIT exon 11 (p.K550_splice) and KIT exon 14 (p.T670I) mutations in GIST-RX2 and KIT exon 9 (p.502_503insYA) and KIT exon 17 (p.D820E) mutations in GIST-RX4 from patients with imatinib and imatinib/sunitinib resistance, respectively. The histological features and mutation statuses of GIST PDXs were consistent with those of the original patient tumors, and the models showed TKI sensitivity comparable to clinical responses. Imatinib inhibited the KIT pathway in imatinib-sensitive GIST-T1 but not GIST-RX1, RX2, and RX4. These GIST PDX models will be useful for studying TKI resistance mechanisms and evaluating novel targeted agents in GIST.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
KIT	D816E	missense	unknown	KIT D816E lies within the protein kinase domain of the Kit protein (UniProt.org). D816E has been identified in the scientific literature (PMID: 29100343, PMID: 29093181) but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT A502_Y503dup	gastrointestinal stromal tumor	predicted - sensitive	Regorafenib	Preclinical - Pdx	Actionable	In a preclinical study, Stivarga (regorafenib) did not significantly inhibit Kit, Erk, or Mtor signaling, but resulted in tumor growth inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup and KIT D820E, which was established from a patient who did not respond to Gleevec (imatinib mesylate) and Sutent (sunitinib) (PMID: 29100343).	29100343
KIT Y570_L576del KIT D816E PTEN T321fs	gastrointestinal stromal tumor	sensitive	Regorafenib	Preclinical - Pdx	Actionable	In a preclinical study, Stivarga (regorafenib) inhibited Kit, Erk, and Mtor signaling, resulted in tumor growth inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT D816E, KIT Y570_L576del, and PTEN T321fs, which was established from a patient who did not respond to Gleevec (imatinib mesylate), Sutent (sunitinib), and Nexavar (sorafenib) (PMID: 29100343).	29100343
KIT exon11 KIT T670I	gastrointestinal stromal tumor	predicted - sensitive	Regorafenib	Preclinical - Pdx	Actionable	In a preclinical study, Stivarga (regorafenib) inhibited Kit signaling, resulted in tumor growth inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT exon 11 mutation (K550_splice) and KIT T670I, which was established from a patient who did not respond to Gleevec (imatinib mesylate) (PMID: 29100343).	29100343
KIT Y570_L576del KIT D816E PTEN T321fs	gastrointestinal stromal tumor	resistant	Sunitinib	Preclinical - Pdx	Actionable	In a preclinical study, Sutent (sunitinib) demonstrated limited inhibition of Kit, Erk, and Mtor signaling and resulted in minimal (22.9%) tumor inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT D816E, KIT Y570_L576del, and PTEN T321fs, which was established from a patient who did not respond to Gleevec (imatinib mesylate), Sutent (sunitinib), and Nexavar (sorafenib) (PMID: 29100343).	29100343
KIT exon11 KIT T670I	gastrointestinal stromal tumor	predicted - sensitive	Sunitinib	Preclinical - Pdx	Actionable	In a preclinical study, Sutent (sunitinib) inhibited Kit signaling, resulted in 86.7% tumor growth inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT exon 11 mutation (K550_splice) and KIT T670I, which was established from a patient who did not respond to Gleevec (imatinib mesylate) (PMID: 29100343).	29100343
KIT exon11 KIT T670I	gastrointestinal stromal tumor	resistant	Imatinib	Preclinical - Pdx	Actionable	In a preclinical study, Gleevec (imatinib mesylate) did not inhibit Kit, Erk signaling and resulted in limited (53.9%) tumor inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT exon 11 mutation (K550_splice) and KIT T670I, which was established from a patient who did not respond to Gleevec (imatinib mesylate) (PMID: 29100343).	29100343
KIT A502_Y503dup KIT D820E	gastrointestinal stromal tumor	predicted - resistant	Sunitinib	Preclinical - Pdx	Actionable	In a preclinical study, Sutent (sunitinib) did not inhibit Kit, Erk, or Mtor signaling and resulted in minimal (26.2%) tumor inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup and KIT D820E, which was established from a patient who did not respond to Gleevec (imatinib mesylate) and Sutent (sunitinib) (PMID: 29100343).	29100343
KIT Y570_L576del KIT D816E PTEN T321fs	gastrointestinal stromal tumor	resistant	Imatinib	Preclinical - Pdx	Actionable	In a preclinical study, Gleevec (imatinib mesylate) did not inhibit Kit, Erk, or Mtor signaling and resulted in minimal tumor inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT D816E, KIT Y570_L576del, and PTEN T321fs, which was established from a patient who did not respond to Gleevec (imatinib mesylate), Sutent (sunitinib), and Nexavar (sorafenib) (PMID: 29100343).	29100343
KIT A502_Y503dup KIT D820E	gastrointestinal stromal tumor	resistant	Imatinib	Preclinical - Pdx	Actionable	In a preclinical study, Gleevec (imatinib mesylate) did not inhibit Kit, Erk, or Mtor signaling and resulted in minimal (7.4%) tumor inhibition in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup and KIT D820E, which was established from a patient who did not respond to Gleevec (imatinib mesylate) and Sutent (sunitinib) (PMID: 29100343).	29100343
KIT Y570_L576del KIT D816E PTEN T321fs	gastrointestinal stromal tumor	sensitive	Imatinib + LY294002	Preclinical - Pdx	Actionable	In a preclinical study, Gleevec (imatinib mesylate) in combination with LY294002 resulted in enhanced tumor growth inhibition compared to monotherapy in patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT D816E, KIT Y570_L576del, and PTEN T321fs, which was established from a patient who did not respond to Gleevec (imatinib mesylate), Sutent (sunitinib), and Nexavar (sorafenib) (PMID: 29100343).	29100343