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Ref Type Journal Article
PMID (23127174)
Authors Ashman LK, Griffith R
Title Therapeutic targeting of c-KIT in cancer.
Journal Vol Issue Date Pages Journal Short Title
Expert opinion on investigational drugs 22 1 2013 Jan 103-15 Expert Opin Investig Drugs
URL
Abstract Text Mutated forms of the receptor tyrosine kinase c-KIT are "drivers" in several cancers and are attractive targets for therapy. While benefits have been obtained from use of inhibitors of KIT kinase activity such as imatinib, especially in gastrointestinal stromal tumours (GIST), primary resistance occurs with certain oncogenic mutations. Furthermore, resistance frequently develops due to secondary mutations. Approaches to addressing both of these issues as well as combination therapies to optimise use of KIT kinase inhibitors are discussed.This review covers the occurrence of oncogenic KIT mutations in different cancers and the molecular basis of their action. The action of KIT kinase inhibitors, especially imatinib, sunitinib, dasatinib and PKC412, on different primary and secondary mutants is discussed. Outcomes of clinical trials in GIST, acute myeloid leukaemia (AML), systemic mastocytosis and melanoma and their implications for future directions are considered.Analysis of KIT mutations in individual patients is an essential prerequisite to the use of kinase inhibitors for therapy, and monitoring for development of secondary mutations that confer drug resistance is necessary. However, it is unlikely that KIT inhibitors alone can lead to cure. KIT mutations alone do not seem to be sufficient for transformation; thus identification and co-targeting of synergistic oncogenic pathways should lead to improved outcomes.

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Molecular Profile Treatment Approach
KIT S501_A502dup KIT Inhibitor
KIT D816G KIT Inhibitor
KIT Q556_D572del KIT Inhibitor
KIT K558_N564del KIT Inhibitor
KIT E562_L576del KIT Inhibitor
KIT I571_L576del KIT Inhibitor
KIT D816N KIT Inhibitor
KIT Y578_D579del KIT Inhibitor
KIT N566_P573del KIT Inhibitor
KIT M552_V555del KIT Inhibitor
KIT D820H KIT Inhibitor
KIT A829P KIT Inhibitor
KIT V559I KIT Inhibitor
KIT P577_D579del KIT Inhibitor
KIT V555_E562del KIT Inhibitor
KIT N567_P573del KIT Inhibitor
KIT Q556_V560delinsH KIT Inhibitor
KIT V560_D572del KIT Inhibitor
KIT I563_L576del KIT Inhibitor
KIT V559K KIT Inhibitor
KIT T417_D419delinsI KIT Inhibitor
KIT T670I KIT Inhibitor
KIT D820G KIT Inhibitor
KIT P551_V555delinsTL KIT Inhibitor
KIT V555_I571del KIT Inhibitor
KIT W557_K558delinsF KIT Inhibitor
KIT C443Y KIT Inhibitor
KIT Y418_D419delinsS KIT Inhibitor
KIT V559_N566delinsD KIT Inhibitor
KIT K509I KIT Inhibitor
KIT Y418_D419delinsG KIT Inhibitor
KIT W557C KIT Inhibitor
KIT Q556_V559delinsHT KIT Inhibitor
KIT W557_V560del KIT Inhibitor
KIT V559G KIT Inhibitor
KIT K558_V559del KIT Inhibitor
KIT R634W KIT Inhibitor
KIT D820V KIT Inhibitor
KIT P551_Q556del KIT Inhibitor
KIT K550_K558del KIT Inhibitor
KIT D572A KIT Inhibitor
KIT V530I KIT Inhibitor
KIT D820Y KIT Inhibitor
KIT V559A KIT Inhibitor
KIT P551_Y553delinsH KIT Inhibitor
KIT Y553N KIT Inhibitor
KIT V560A KIT Inhibitor
KIT exon 11 del KIT Inhibitor
KIT E554_Y570del KIT Inhibitor
KIT E554_K558del KIT Inhibitor
KIT H697Y KIT Inhibitor
KIT M552_Y570del KIT Inhibitor
KIT P551_W557delinsL KIT Inhibitor
KIT L576del KIT Inhibitor
KIT T417_Y418delinsH KIT Inhibitor
KIT E490K KIT Inhibitor
KIT L576P KIT Inhibitor
KIT T417_D419delinsRA KIT Inhibitor
KIT Y553_Q556del KIT Inhibitor
KIT D816Y KIT Inhibitor
KIT N564_Y578del KIT Inhibitor
KIT M552_E554delinsK KIT Inhibitor
KIT Y570_L576del KIT Inhibitor
KIT V555_P573del KIT Inhibitor
KIT N655K KIT Inhibitor
KIT Q556_K558del KIT Inhibitor
KIT V560_L576del KIT Inhibitor
KIT N564_L576del KIT Inhibitor
KIT W557_V559del KIT Inhibitor
KIT K558_E562del KIT Inhibitor
KIT Y570_Y578del KIT Inhibitor
KIT D579del KIT Inhibitor
KIT V555_Q556del KIT Inhibitor
KIT Q556_V560del KIT Inhibitor
KIT P551_K558delinsQ KIT Inhibitor
KIT V560G KIT Inhibitor
KIT N822I KIT Inhibitor
KIT A502_Y503dup KIT Inhibitor
KIT Y568_L576delinsCV KIT Inhibitor
KIT V559_E561del KIT Inhibitor
KIT V560D KIT Inhibitor
KIT V569_L576del KIT Inhibitor
KIT M552_V555delinsI KIT Inhibitor
KIT Q556_V559del KIT Inhibitor
KIT K558_Y570delinsR KIT Inhibitor
KIT M552_E554del KIT Inhibitor
KIT S628N KIT Inhibitor
KIT amp KIT Inhibitor
KIT W557S KIT Inhibitor
KIT K558_G565delinsR KIT Inhibitor
KIT M552_Q556del KIT Inhibitor
KIT M552_V559del KIT Inhibitor
KIT V825A KIT Inhibitor
KIT P577del KIT Inhibitor
KIT K558_D572del KIT Inhibitor
KIT P551_M552delinsL KIT Inhibitor
KIT W557G KIT Inhibitor
KIT Y553_E554del KIT Inhibitor
KIT Y553_E561delinsLK KIT Inhibitor
KIT W557_K558delinsC KIT Inhibitor
KIT K550_V559del KIT Inhibitor
KIT S476I KIT Inhibitor
KIT D816I KIT Inhibitor
KIT M552_E554delinsI KIT Inhibitor
KIT V555_V560del KIT Inhibitor
KIT V555_D572del KIT Inhibitor
KIT K558_Y570delinsN KIT Inhibitor
KIT Y823D KIT Inhibitor
KIT S501_A502insSAY KIT Inhibitor
KIT V560_Y578del KIT Inhibitor
KIT D820A KIT Inhibitor
KIT W557R KIT Inhibitor
KIT Y553_W557del KIT Inhibitor
KIT act mut KIT Inhibitor
KIT Y578C KIT Inhibitor
KIT V559_T574del KIT Inhibitor
KIT Y553_K558del KIT Inhibitor
KIT M552_W557del KIT Inhibitor
KIT K558delinsNP KIT Inhibitor
KIT K550_V555delinsI KIT Inhibitor
KIT F522C KIT Inhibitor
KIT T417_D419delinsY KIT Inhibitor
KIT V560E KIT Inhibitor
KIT M552_K558del KIT Inhibitor
KIT Q556_V559delinsH KIT Inhibitor
KIT M552_Y553del KIT Inhibitor
KIT K550_E554del KIT Inhibitor
KIT Y568_T574del KIT Inhibitor
KIT V559D KIT Inhibitor
KIT N822Y KIT Inhibitor
KIT D816F KIT Inhibitor
KIT K558_Y570delinsNP KIT Inhibitor
KIT E554_D572delinsA KIT Inhibitor
KIT Q556_W557del KIT Inhibitor
KIT M552_V559delinsI KIT Inhibitor
KIT W557_K558del KIT Inhibitor
KIT V559_P573del KIT Inhibitor
KIT W557_K558delinsE KIT Inhibitor
KIT P551_E554del KIT Inhibitor
KIT V559_V560del KIT Inhibitor
KIT W557_Q575del KIT Inhibitor
KIT V560del KIT Inhibitor
KIT K550_P551del KIT Inhibitor
KIT V559_G565del KIT Inhibitor
KIT P551_V555del KIT Inhibitor
KIT K558_V560del KIT Inhibitor
KIT K642E KIT Inhibitor
KIT W557_E561del KIT Inhibitor
KIT D419del KIT Inhibitor
KIT Q556_I571del KIT Inhibitor
KIT Y823N KIT Inhibitor
KIT D816E KIT Inhibitor
KIT M552_D572del KIT Inhibitor
KIT Q556_L576del KIT Inhibitor
KIT W557del KIT Inhibitor
KIT D60N KIT Inhibitor
KIT N822K KIT Inhibitor
KIT V559_V560delinsS KIT Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
KIT NCBI C-Kit|CD117|MASTC|PBT|SCFR KIT, KIT proto-oncogene, receptor tyrosine kinase, is a transmembrane receptor tyrosine kinase (PMID: 32214210) that binds the stem cell factor (SCF) ligand to activate PI3K, JAK/STAT, and MAPK pathways to promote cell survival and proliferation (PMID: 23181448, PMID: 29704617). Activating Kit mutations are driver mutations in a variety of cancers, particularly in gastrointestinal stromal tumors (PMID: 23127174, PMID: 29704617, PMID: 32091431), acute myeloid leukemia (PMID: 32008291), melanomas (PMID: 30707374, PMID: 32608199), and seminomas (PMID: 29704617). Oncogene
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Midostaurin Rydapt PKC412|CGP 41251 CSF1R Inhibitor 28 FLT3 Inhibitor 69 KIT Inhibitor 57 PKC alpha Inhibitor 6 PKC beta Inhibitor 6 PKC Inhibitor (Pan) 11 VEGFR2 Inhibitor 37 Rydapt (midostaurin) is a multi-kinase inhibitor with activity against FLT3, KIT, PDGFRB, KDR (VEGFR2) and PKC, with higher selectivity for conventional PKC isoforms, which induces cell cycle arrest and apoptosis (PMID: 12124173, PMID: 23127174, PMID: 15914319). Rydapt (midostaurin) is FDA approved for FLT3-mutant AML in combination with chemotherapy, and is approved for use in aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia as a single therapy (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References