title: PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.
abstract: Targeting 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 screen to identify genes that rescue HER2-amplified breast cancer cells from HER2 inhibition or suppression. In addition to multiple members of the MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) 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, the BCl-2-associated death promoter, 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.
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Moody
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Schinzel
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Strickland
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Thomas
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: J S
authors.identifier: 0000000267956336
authors.initials: JS
authors.lastname: Boehm
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Bringham and Women's Hospital and Harvard Medical School, Boston, MA, USA [3] Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D051025:bcl-Associated Death Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C508053:ERBB2 protein, human; C496634:PIM1 protein, human; C517757:PRKACA protein, human