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dc.contributor.authorMoody, Susan E.en_US
dc.contributor.authorSchinzel, Anna C.en_US
dc.contributor.authorSingh, Shambhavien_US
dc.contributor.authorIzzo, Francescaen_US
dc.contributor.authorStrickland, Matthew R.en_US
dc.contributor.authorLuo, Leoen_US
dc.contributor.authorThomas, Sapana R.en_US
dc.contributor.authorBoehm, Jesse S.en_US
dc.contributor.authorKim, So Youngen_US
dc.contributor.authorWang, Zhigang C.en_US
dc.contributor.authorHahn, William C.en_US
dc.date.accessioned2015-11-03T15:58:20Z
dc.date.issued2014en_US
dc.identifier.citationMoody, S. E., A. C. Schinzel, S. Singh, F. Izzo, M. R. Strickland, L. Luo, S. R. Thomas, et al. 2014. “PRKACA Mediates Resistance to HER2-Targeted Therapy in Breast Cancer Cells and Restores Anti-Apoptotic Signaling.” Oncogene 34 (16): 2061-2071. doi:10.1038/onc.2014.153. http://dx.doi.org/10.1038/onc.2014.153.en
dc.identifier.issn0950-9232en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:23474015
dc.description.abstractTargeting HER2 with antibodies or small molecule inhibitors in HER2-positive breast cancer leads to improved survival, but resistance is a common clinical problem. To uncover novel mechanisms of resistance to anti-HER2 therapy in breast cancer, we performed a kinase open reading frame (ORF) screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK and PI3K signaling pathways, we discovered that expression of the survival kinases PRKACA and PIM1 rescued cells from anti-HER2 therapy. Furthermore, we observed elevated PRKACA expression in trastuzumab-resistant breast cancer samples, indicating that this pathway is activated in breast cancers that are clinically resistant to trastuzumab-containing therapy. We found that neither PRKACA nor PIM1 restored MAPK or PI3K activation after lapatinib or trastuzumab treatment, but rather inactivated the pro-apoptotic protein BAD, thereby permitting survival signaling through BCL-XL. Pharmacological blockade of BCL-XL/BCL-2 partially abrogated the rescue effects conferred by PRKACA and PIM1, and sensitized cells to lapatinib treatment. These observations suggest that combined targeting of HER2 and the BCL-XL/BCL-2 anti-apoptotic pathway may increase responses to anti-HER2 therapy in breast cancer and decrease the emergence of resistant disease.en
dc.language.isoen_USen
dc.relation.isversionofdoi:10.1038/onc.2014.153en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261061/pdf/en
dash.licenseLAAen_US
dc.subjectbreast canceren
dc.subjectdrug resistanceen
dc.subjectHER2en
dc.subjectPRKACAen
dc.subjectPIM1en
dc.titlePRKACA Mediates Resistance to HER2-Targeted Therapy in Breast Cancer Cells and Restores Anti-Apoptotic Signalingen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalOncogeneen
dash.depositing.authorMoody, Susan E.en_US
dc.date.available2015-11-03T15:58:20Z
dc.identifier.doi10.1038/onc.2014.153*
dash.authorsorderedfalse
dash.identifier.orcid0000-0002-3061-4287en_US
dash.contributor.affiliatedLuo, Leo Y.
dash.contributor.affiliatedHahn, William
dash.contributor.affiliatedWang, Zhigang C.
dash.contributor.affiliatedMoody, Susan E
dc.identifier.orcid0000-0002-3061-4287


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