PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling

Oncogene. 2015 Apr 16;34(16):2061-71. doi: 10.1038/onc.2014.153. Epub 2014 Jun 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / physiology*
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Lapatinib
  • Mitogen-Activated Protein Kinases / genetics
  • Open Reading Frames / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphorylation
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Quinazolines / therapeutic use*
  • Receptor, ErbB-2 / antagonists & inhibitors*
  • Trastuzumab
  • bcl-Associated Death Protein / antagonists & inhibitors
  • bcl-Associated Death Protein / metabolism
  • bcl-X Protein / antagonists & inhibitors

Substances

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • BAD protein, human
  • BCL2L1 protein, human
  • Protein Kinase Inhibitors
  • Quinazolines
  • bcl-Associated Death Protein
  • bcl-X Protein
  • Lapatinib
  • Phosphatidylinositol 3-Kinases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • PRKACA protein, human
  • Mitogen-Activated Protein Kinases
  • Trastuzumab