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Ref Type Journal Article
PMID (18294292)
Authors Nishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, Hirota S
Title Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor.
Journal Cancer science
Vol 99
Issue 4
Date 2008 Apr
URL
Abstract Text Although imatinib showed high activity for advanced gastrointestinal stromal tumor (GIST) and improved the prognosis of GIST patients, resistance to the drug appears with prolonged use. Mechanisms of acquired resistance are still under investigation. In the present study, we carried out histologic and genetic analysis of 45 secondary resistant lesions obtained from 25 Japanese GIST patients treated with imatinib. All resistant lesions showed viable tumor cells expressing KIT protein, whereas imatinib-sensitive lesions did not. All pre-imatinib samples have KIT mutations either in exon 9 (n = 3) or exon 11 (n = 22), identified in the KIT gene of corresponding resistant tumors. In addition to primary mutations, 33 out of 45 tumors (73%) showed secondary KIT mutations in the kinase domain of the KIT gene. Secondary mutations are missense mutations and are mostly located in the kinase domains of the same allele to the primary mutations (cis-position). Resistant lesions showed monoclonal development of tumor cells. Taken together, additional cis-positioned mutations in the kinase domains are a major cause of secondary resistance to imatinib in Japanese GIST patients.

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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 D820V missense unknown KIT D820V lies within the protein kinase domain of the Kit protein (UniProt.org). D820V has been identified as a secondary mutation associated with imatinib resistance (PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Oct 2022). Y
KIT K558N missense unknown KIT K558N lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). K558N has been identified in sequencing studies (PMID: 21326036, PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Oct 2022).
KIT N822D missense unknown KIT N822D lies within the protein kinase domain of the Kit protein (UniProt.org). N822D has been identified in the scientific literature (PMID: 35091442, PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Oct 2022).
KIT P551I missense unknown KIT P551I lies within the juxtamembrane domain of the Kit protein (PMID: 16226710). P551I has been identified as a secondary mutation associated with imatinib resistance (PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Oct 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT V560_D572del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumors harboring KIT V560_D572del, with a progression-free survival of 16.5 months and an overall survival of 57.4 months (PMID: 18294292). 18294292
KIT Q556_W557del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT Q556_W557del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT V654A (PMID: 18294292). 18294292
KIT P551I KIT M552_V559del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumors harboring KIT M552_V559del and KIT P551I, with a progression-free survival of 9 months and an overall survival of 19.5 months (PMID: 18294292). 18294292
KIT W557_K558del KIT D816H gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT W557_K558del progressed after experiencing stable disease on treatment with Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT D816H (PMID: 18294292). 18294292
KIT W557_E561del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, two patients with gastrointestinal stromal tumors harboring KIT W557_E561del progressed following an initial response to Gleevec (imatinib), and were found to have acquired the secondary resistance mutation KIT V654A (PMID: 18294292). 18294292
KIT K558N KIT V560del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumors harboring KIT K558N and KIT V560del (reported as KIT V559del), with a progression-free survival of 23.4 months and an overall survival of 54.7 months (PMID: 18294292). 18294292
KIT V560del KIT N822K gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT V560del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT N822K (PMID: 18294292). 18294292
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, two patients with gastrointestinal stromal tumors harboring KIT W557_K558del progressed following an initial response to Gleevec (imatinib), and were found to have acquired the secondary resistance mutation KIT Y823D in one lesion (PMID: 18294292). 18294292
KIT M552_D572del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to partial responses in two patients with gastrointestinal stromal tumors harboring KIT M552_D572del, with a progression-free survival (PFS) of 25.2 mo and overall survival (OS) of 32 mo in one patient, and a PFS of 50.9 mo and OS of 53.9 mo in the second patient (PMID: 18294292). 18294292
KIT W557_E561del KIT N822D gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT W557_E561del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT N822D (PMID: 18294292). 18294292
KIT E554_Y570del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT E554_Y570del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT V654A (PMID: 18294292). 18294292
KIT W557_E561del gastrointestinal stromal tumor sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to partial responses in two patients with gastrointestinal stromal tumors harboring KIT W557_E561del, with a progression-free survival (PFS) of 10.7 mo and overall survival (OS) of 14.9 mo in one patient, and a PFS of 32.2 mo and OS of 34.4 mo in the second patient (PMID: 18294292). 18294292
KIT W557_K558del KIT D816E KIT D820V gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical study, KIT D816E and D820V were identified as secondary mutations in a patient with gastrointestinal stromal tumor harboring KIT W557_K558del who developed resistance to Gleevec (imatinib) (PMID: 18294292). 18294292
KIT V555_D572del KIT N822K gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT V555_D572del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT N822K (PMID: 18294292). 18294292
KIT V559_T574del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT V559_T574del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT V654A in one lesion (PMID: 18294292). 18294292
KIT Y570_Y578del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumors harboring KIT Y570_Y578del, with a progression-free survival of 19.1 months and an overall survival of 53.2 months (PMID: 18294292). 18294292
KIT E554_Y570del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumor harboring KIT E554_Y570del, with a progression-free survival of 11.5 months and overall survival of 34.1 months (PMID: 18294292). 18294292
KIT W557_K558del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment resulted in 4 partial responses and 1 stable disease in 5 patients with gastrointestinal stromal tumors harboring KIT W557_K558del, with progression-free survival ranging from 12.2 to 36.5 months and overall survival ranging from 22.7 to 67.9 months (PMID: 18294292). 18294292
KIT V560_D572del KIT A829P gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT KIT V560_D572del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT A829P (PMID: 18294292). 18294292
KIT P551I KIT M552_V559del KIT Y823D gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT M552_V559del and KIT P551I progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT Y823D (PMID: 18294292). 18294292
KIT W557_K558del KIT T670I gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT W557_K558del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT T670I (PMID: 18294292). 18294292
KIT V555_D572del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumor harboring KIT V555_D572del, with a progression-free survival of 49.4 mo and an overall survival of 59.3 mo (PMID: 18294292). 18294292
KIT V559_T574del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a partial response in a patient with gastrointestinal stromal tumors harboring KIT V559_T574del, with a progression-free survival of 28 months and an overall survival of 54.9 months (PMID: 18294292). 18294292
KIT V555_D572del KIT N822Y gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, a patient with gastrointestinal stromal tumor harboring KIT V555_D572del progressed following an initial response to Gleevec (imatinib), and was found to have acquired the secondary resistance mutation KIT N822Y (PMID: 18294292). 18294292
KIT Q556_W557del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment resutled in a partial response in a patient with gastrointestinal stromal tumor harboring KIT Q556_W557del , with a progression-free survival of 26.8 months and an overall survival of 47 months (PMID: 18294292). 18294292
KIT W557_K558del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, three patients with gastrointestinal stromal tumors harboring KIT W557_K558del progressed following an initial response to Gleevec (imatinib), and were found to have acquired the secondary resistance mutation KIT V654A (PMID: 18294292). 18294292
KIT V560del gastrointestinal stromal tumor predicted - sensitive Imatinib Case Reports/Case Series Actionable In a clinical case study, Gleevec (imatinib) treatment led to a complete response in a patient with gastrointestinal stromal tumor harboring KIT V560del, with a progression-free survival of 33.4 months and an overall survival of 46.8 months (PMID: 18294292). 18294292
KIT M552_D572del KIT V654A gastrointestinal stromal tumor predicted - resistant Imatinib Case Reports/Case Series Actionable In a clinical case study, two patients with gastrointestinal stromal tumors harboring KIT M552_D572del progressed following an initial response to Gleevec (imatinib), and were found to have acquired the secondary resistance mutation KIT V654A (PMID: 18294292). 18294292