Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Johnson, Katherine J.; Kumar, Vikas; Kurimchak, Alison; Srivastava, N. K.; Peri, Suraj; Cai, Kathy Q.; Mantia‐Smaldone, Gina; Duncan, James S.

doi:10.1101/2020.03.03.970251

Cited by 2 publications

(2 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this work, using MIB-MS (19,20), we explored a high percentage (296/518) of the human kinome in treatment naïve primary GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and SDH-d GIST) in order to identify potential novel targets. Using this proteomics approach, we demonstrated that the three GIST subtypes have distinct kinome profiles, and identified kinases that are universally overexpressed in all GIST, as well as kinases that are unique to each subtype.…”

Section: Introductionmentioning

confidence: 99%

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Ye¹,

Sharipova²,

Kozinova³

et al. 2021

JCI Insight

Self Cite

View full text Add to dashboard Cite

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes ( KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G 2 /M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Ye¹,

Sharipova²,

Kozinova³

et al. 2021

JCI Insight

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this work, using MIB-MS (19,20), we explored the majority of the kinome in treatment naïve primary GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and SDH-d GIST) in order to identify potential novel targets. Using this proteomics approach, we demonstrated that the three GIST subtypes have distinct kinome profiles, and identified kinases that are universally activated in all GIST, as well as kinases that are unique to each subtype.…”

Section: Introductionmentioning

confidence: 99%

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Sharipova

Kozinova

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Gastrointestinal stromal tumor (GIST) management has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of receptor tyrosine kinase (RTK) inhibitors in advanced disease. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GIST, resistance remains a significant clinical obstacle.Development of effective strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes.PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a monotherapy in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

show abstract

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target

Cited by 2 publications

References 59 publications

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Contact Info

Product

Resources

About