PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Moody, SE; Schinzel, AC; Singh, S; Izzo, F; Strickland, MR; Luo, L; Thomas, SR; Boehm, JS; Kim, SY; Wang, ZC; Hahn, WC
Published Date
- April 16, 2015
Published In
Volume / Issue
- 34 / 16
Start / End Page
- 2061 - 2071
PubMed ID
- 24909179
Pubmed Central ID
- PMC4261061
Electronic International Standard Serial Number (EISSN)
- 1476-5594
Digital Object Identifier (DOI)
- 10.1038/onc.2014.153
Language
- eng
Conference Location
- England