Dataset Information

Characterization of WSD-0922 Signaling

ABSTRACT: The present pre-clinicial study sought to evaluate the novel EGFR inhibitor WSD-0922. We employed flank and orthotopic patient derived xenograft (PDX) models to characterize WSD-0922 and compare its therapeutic efficacy to erlotinib, a potent EGFR inhibitor that failed to provide clinical benefit for GBM patients. We utilized phosphotyrosine mass spectrometry analyses to measure the impact of each drug on receptor activity and cellular signaling networks.

INSTRUMENT(S): Q Exactive HF, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Jason Conage-Pough

LAB HEAD: Forest Michael White

PROVIDER: PXD032974 | Pride | 2023-06-21

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	JCP_012022_AC7_PC13_GBM12_IC_erlotinibvswsd_repeat_TMT11_supe.mzML	Mzml
	JCP_012022_AC7_PC13_GBM12_IC_erlotinibvswsd_repeat_TMT11_supe.mzid.gz	Mzid
	JCP_012022_AC7_PC13_GBM12_IC_erlotinibvswsd_repeat_TMT11_supe.raw	Raw
	JCP_012022_ACcheck_pY_GBM12_IC_erlotinibvswsd_repeat_11plex.mzML	Mzml
	JCP_012022_ACcheck_pY_GBM12_IC_erlotinibvswsd_repeat_11plex.mzid.gz	Mzid

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Publications

WSD-0922, a novel brain-penetrant inhibitor of epidermal growth factor receptor, promotes survival in glioblastoma mouse models.

Conage-Pough Jason E JE Stopka Sylwia A SA Oh Ju-Hee JH Mladek Ann C AC Burgenske Danielle M DM Regan Michael S MS Baquer Gerard G Decker Paul A PA Carlson Brett L BL Bakken Katrina K KK Zhang Jinqiang J Liu Lily L Sun Claire C Mu Zhihua Z Zhong Wei W Tran Nhan L NL Elmquist William F WF Agar Nathalie Y R NYR Sarkaria Jann N JN White Forest M FM

Neuro-oncology advances 20230101 1

<h4>Background</h4>Although the epidermal growth factor receptor (EGFR) is a frequent oncogenic driver in glioblastoma (GBM), efforts to therapeutically target this protein have been largely unsuccessful. The present preclinical study evaluated the novel EGFR inhibitor WSD-0922.<h4>Methods</h4>We employed flank and orthotopic patient-derived xenograft models to characterize WSD-0922 and compare its efficacy to erlotinib, a potent EGFR inhibitor that failed to provide benefit for GBM patients. We ...[more]

PMID: 37324218

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Project description:Lung cancer is the leading cause of cancer death. Mutations in the kinase domain of EGFR, a predominant driver oncogene, such as L858R missense mutation and a series of deletions spanning the conserved sequence 747LREA750, are associated with sensitivity to tyrosine kinase inhibitors (TKIs). However, patients receiving EGFR-TKIs (gefitinib and erlotinib) develop drug-resistance due to a secondary mutation at the gatekeeper residue (T790M) in about 50-60% of cases, urging for new drug development. Afatinib, a FDA approved second-generation EGFR-TKI that was developed to circumvent T790M-mediated resistance, has not been very effective in clinical trials. In this study, we performed a global phosphoproteomic screen to identify targets that undergo mutant EGFR-dependent tyrosine phosphorylation and their modulation by erlotinib or afatinib. We undertook stable isotope labeling of amino acids in cell culture (SILAC), phosphopeptide enrichment, and quantitative mass spectrometry to identify dynamic changes of phosphorylation downstream of mutant EGFRs in lung adenocarcinoma cells harboring L858R or L858R/T790M mutations and their modulation by erlotinib and afatinib inhibition. We identified and quantified 397, 429, 223, and 594 phosphotyrosine sites in H3255, 11-18,PC9, and H1975 cell lines that were grown in presence of FBS and in presence/absence of TKIs, respectively. These account for a total of 907 unique phospho-tyrosine sites in 496 proteins. Among them, 187 phosphotyrosine sites were found to be in 89 kinases, which may serve as intermediary regulatory kinases in EGFR signalling pathway. Further analysis indicated that in TKI-sensitive H3255 and 11-18 cells, there were 58/111 and 65/101 tyrosine sites that were hypophosphorylated in presence of erlotinib and afatinib, respectively. However, in TKI-resistant H1975 cells, 189 and 264 tyrosine sites were hypophosphorylated in presence of erlotinib and afatinib respectively, indicating that the afatinib-specific additional sites could be validated for identifying potentially new drug targets to counter TKI-resistance. Ingenuity pathway analysis (IPA) of proteins with altered phosphorylation sites demonstrated that several canonical pathways including ephrin receptor signalling and integrin signalling pathways were enriched, which may play important roles in cell growth and proliferation. However, upon EGF stimulation of serum starved H3255 cells in presence or absence of TKIs, 99 tyrosine sites that were hyperphosphorylated upon EGF stimulation were inhibited in presence of erlotinib or afatinib. But in H1975 cells treated with erlotinib, 48 of the above sites were either unchanged or were hyperphosphorylated. These sites include EGFR (Y1197/869/998), JAK1 (Y1034), FRK (Y497), GAB1 (Y657/689), MAPK1 (Y187), MAPK3 (Y204), MET (Y1252/1253). Furthermore, a total of 112 sites that were observed to be hypophosphorylated upon EGF stimulation in H1975 cells, were found to be hyperphosphorylated upon erlotinib inhibition. This could possibly be due to the activation of downstream phosphatases with EGF stimulation. We are now performing in-depth bioinformatic analysis and validation experiments using functional genomics to understand the role of targets of mutant EGFR signalling in lung cancer.