- Title
- Pharmaco-phosphoproteomic analysis of cancer-associated KIT mutations D816V and V560G
- Creator
- Murray, Heather C.; Miller, Kasey; Dun, Matthew D.; Verrills, Nicole M.
- Relation
- Proteomics Vol. 24, Issue 9, no. 2300309
- Publisher Link
- http://dx.doi.org/10.1002/pmic.202300309
- Publisher
- Wiley-VCH Verlag GmbH
- Resource Type
- journal article
- Date
- 2024
- Description
- The CD117 mast/stem cell growth factor receptor tyrosine kinase (KIT) is critical for haematopoiesis, melanogenesis and stem cell maintenance. KIT is commonly activated by mutation in cancers including acute myeloid leukaemia, melanoma and gastrointestinal stromal tumours (GISTs). The kinase and the juxtamembrane domains of KIT are mutation hotspots; with the kinase domain mutation D816V common in leukaemia and the juxtamembrane domain mutation V560G common in GISTs. Given the importance of mutant KIT signalling in cancer, we have conducted a proteomic and phosphoproteomic analysis of myeloid progenitor cells expressing D816V- and V560G-KIT mutants, using an FDCP1 isogenic cell line model. Proteomic analysis revealed increased abundance of proteases and growth signalling proteins in KIT-mutant cells compared to empty vector (EV) controls. Pathway analysis identified increased oxidative phosphorylation in D816V- and V560G-mutant KIT cells, which was targetable using the inhibitor IACS010759. Dysregulation of RNA metabolism and cytoskeleton/adhesion pathways was identified in both the proteome and phosphoproteome of KIT-mutant cells. Phosphoproteome analysis further revealed active kinases such as EGFR, ERK and PKC, which were targetable using pharmacological inhibitors. This study provides a pharmaco-phosphoproteomic profile of D816V- and V560G-mutant KIT cells, which reveals novel therapeutic strategies that may be applicable to a range of cancers.
- Subject
- cancer; CD117; proteomics; leukaemia; phosphoproteomics; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1504097
- Identifier
- uon:55444
- Identifier
- ISSN:1615-9853
- Rights
- x
- Language
- eng
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