A phosphotyrosine proteomic screen identifies multiple tyrosine kinase signaling pathways aberrantly activated in malignant mesothelioma

Craig W. Menges, Yibai Chen, Brooke T. Mossman, Jonathan Chernoff, Anthony T. Yeung, Joseph R. Testa

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Malignant mesothelioma (MM) is a highly aggressive cancer that is refractory to all current chemotherapeutic regimens. Therefore, uncovering new rational therapeutic targets is imperative in the field. Tyrosine kinase signaling pathways are aberrantly activated in many human cancers and are currently being targeted for chemotherapeutic intervention. Thus, we sought to identify tyrosine kinases hyperactivated in MM. An unbiased phosphotyrosine proteomic screen was employed to identify tyrosine kinases activated in human MM cell lines. From this screen, we have identified novel signaling molecules, such as JAK1, STAT1, cortactin (CTTN), FER, p130Cas (BCAR1), SRC, and FYN as tyrosine phosphorylated in human MM cell lines. Additionally, STAT1 and SRC family kinases (SFK) were confirmed to be active in primary MM specimens. We also confirmed that known signal transduction pathways previously implicated in MM, such as EGFR and MET signaling axes, are coactivated in the majority of human MM specimens and cell lines tested. EGFR, MET, and SFK appear to be coactivated in a significant proportion of MM cell lines, and dual inhibition of these kinases was demonstrated to be more efficacious for inhibiting MM cell viability and downstream effector signaling than inhibition of a single tyrosine kinase. Consequently, these data suggest that tyrosine kinase inhibitor monotherapy may not represent an efficacious strategy for the treatment of MM due to multiple tyrosine kinases potentially signaling redundantly to cellular pathways involved in tumor cell survival and proliferation.

Original languageEnglish
Pages (from-to)493-505
Number of pages13
JournalGenes and Cancer
Volume1
Issue number5
DOIs
StatePublished - 2010

Keywords

  • Asbestos
  • Coactivation
  • Mesothelioma
  • Proteomics
  • Tyrosine kinases

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