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dc.contributor.authorSos, Martin L.
dc.contributor.authorFischer, Stefanie
dc.contributor.authorUllrich, Roland
dc.contributor.authorPeifer, Martin
dc.contributor.authorHeuckmann, Johannes M.
dc.contributor.authorKoker, Mirjam
dc.contributor.authorHeynck, Stefanie
dc.contributor.authorStückrath, Isabel
dc.contributor.authorWeiss, Jonathan
dc.contributor.authorFischer, Florian
dc.contributor.authorMichel, Kathrin
dc.contributor.authorGoel, Aviva
dc.contributor.authorRegales, Lucia
dc.contributor.authorPoliti, Katerina A.
dc.contributor.authorPerera, Samanthi
dc.contributor.authorGetlik, Matthäus
dc.contributor.authorHeukamp, Lukas C.
dc.contributor.authorAnsén, Sascha
dc.contributor.authorZander, Thomas
dc.contributor.authorBeroukhim, Rameen
dc.contributor.authorKashkar, Hamid
dc.contributor.authorShokat, Kevan M.
dc.contributor.authorSellers, William R.
dc.contributor.authorRauh, Daniel
dc.contributor.authorOrr, Christine
dc.contributor.authorHoeflich, Klaus P.
dc.contributor.authorFriedman, Lori
dc.contributor.authorWong, Kwok-Kin
dc.contributor.authorPao, William
dc.contributor.authorThomas, Roman K.
dc.date.accessioned2019-10-05T03:27:40Z
dc.date.issued2009
dc.identifier.citationSos, M. L., S. Fischer, R. Ullrich, M. Peifer, J. M. Heuckmann, M. Koker, S. Heynck, et al. 2009. “Identifying Genotype-Dependent Efficacy of Single and Combined PI3K- and MAPK-Pathway Inhibition in Cancer.” Proceedings of the National Academy of Sciences 106 (43): 18351–56. https://doi.org/10.1073/pnas.0907325106.
dc.identifier.issn0027-8424
dc.identifier.issn0744-2831
dc.identifier.issn1091-6490
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41482953*
dc.description.abstractIn cancer, genetically activated proto-oncogenes often induce "upstream'' dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce "downstream'' dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
dc.language.isoen_US
dc.publisherNational Academy of Sciences
dash.licenseLAA
dc.titleIdentifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer
dc.typeJournal Article
dc.description.versionVersion of Record
dc.relation.journalProceedings of the National Academy of Sciences of the United States of America
dash.depositing.authorBeroukhim, Rameen::c5fb52f8c466a3133522637bebc1675a::600
dc.date.available2019-10-05T03:27:40Z
dash.workflow.comments1Science Serial ID 90402
dc.identifier.doi10.1073/pnas.0907325106
dash.source.volume106;43
dash.source.page18351


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