title: Identification of kinase inhibitor targets in the lung cancer microenvironment by chemical and phosphoproteomics.
abstract: A growing number of gene mutations, which are recognized as cancer drivers, can be successfully targeted with drugs. The redundant and dynamic nature of oncogenic signaling networks and complex interactions between cancer cells and the microenvironment, however, can cause drug resistance. While these challenges can be addressed by developing drug combinations or polypharmacology drugs, this benefits greatly from a detailed understanding of the proteome-wide target profiles. Using mass spectrometry-based chemical proteomics, we report the comprehensive characterization of the drug-protein interaction networks for the multikinase inhibitors dasatinib and sunitinib in primary lung cancer tissue specimens derived from patients. We observed in excess of 100 protein kinase targets plus various protein complexes involving, for instance, AMPK, TBK1 (sunitinib), and ILK (dasatinib). Importantly, comparison with lung cancer cell lines and mouse xenografts thereof showed that most targets were shared between cell lines and tissues. Several targets, however, were only present in tumor tissues. In xenografts, most of these proteins were of mouse origin suggesting that they originate from the tumor microenvironment. Furthermore, intersection with subsequent global phosphoproteomic analysis identified several activated signaling pathways. These included MAPK, immune, and integrin signaling, which were affected by these drugs in both cancer cells and the microenvironment. Thus, the combination of chemical and phosphoproteomics can generate a systems view of proteins, complexes, and signaling pathways that are simultaneously engaged by multitargeted drugs in cancer cells and the tumor microenvironment. This may allow for the design of novel anticancer therapies that concurrently target multiple tumor compartments.
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Gridling
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Florian P
authors.initials: FP
authors.lastname: Breitwieser
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Lanxi
authors.initials: L
authors.lastname: Song
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Katja
authors.initials: K
authors.lastname: Parapatics
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria. Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Uwe.Rix@moffitt.org.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040901:Proteomics; D015398:Signal Transduction; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases