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 Oncotarget
Vol 8
Issue 44
Date 2017 Sep 29
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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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, Mar 2019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT exon 11 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 D816E KIT Y570_L576del PTEN T321fs gastrointestinal stromal tumor sensitive Imatinib + LY294002 Preclinical - Pdx Actionable In a preclinical study, Gleevec (imatinib mesylate) in combination with LY394002 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
KIT exon 11 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 D816E KIT Y570_L576del 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 D816E KIT Y570_L576del 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 D816E KIT Y570_L576del 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 exon 11 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 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 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