Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells.

Ming Zhao,Erin W Howard,Zhiying Guo,Qingxia Zhao,Ann D Thor,Susan M Edgerton,Bolin Liu,Xiaohe Yang,Amanda B Parris,Ying Xing,Zhikun Ma

doi:10.18632/oncotarget.19375

Abstract

Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer. Our study investigated the role of CIP2A in the anti-cancer efficacy of lapatinib in ErbB2-overexpressing breast cancer cells. We found that lapatinib concurrently downregulated CIP2A and receptor tyrosine kinase signaling in ErbB2-overexpressing SKBR3 and 78617 cells; however, these effects were attenuated in lapatinib-resistant (LR) cells. CIP2A overexpression rendered SKBR3 and 78617 cells resistant to lapatinib-induced apoptosis and growth inhibition. Conversely, CIP2A knockdown via lentiviral shRNA enhanced cell sensitivity to lapatinib-induced growth inhibition and apoptosis. Results also suggested that lapatinib downregulated CIP2A through regulation of protein stability. We further demonstrated that lapatinib-induced CIP2A downregulation can be recapitulated by LY294002, suggesting that Akt mediates CIP2A upregulation. Importantly, lapatinib induced differential CIP2A downregulation between parental BT474 and BT474/LR cell lines. Moreover, CIP2A shRNA knockdown significantly sensitized the BT474/LR cells to lapatinib. Collectively, our results demonstrate that CIP2A is a molecular target and resistance factor of lapatinib with a critical role in lapatinib-induced cellular responses, including the inhibition of the CIP2A-Akt feedback loop. Further investigation of lapatinib-mediated CIP2A regulation will advance our understanding of lapatinib-associated anti-tumor activities and drug resistance.

Highlights

ErbB2 is a receptor tyrosine kinase (RTK) belonging to the epidermal growth factor receptor (EGFR) family, which is comprised of four members: EGFR/ErbB1, ErbB2/Her2/Neu, ErbB3, and ErbB4 [1, 2]
We examined the role of Cancerous inhibitor of protein phosphatase 2A (CIP2A) in lapatinibinduced anti-cancer effects in ErbB2-overexpressing SKBR3 human breast cancer cells and 78617 cells, which are derived from spontaneous mammary tumors of MMTV-ErbB2 transgenic mice [31]
We found that lapatinib induces CIP2A downregulation in a concentration-dependent manner, which is correlated with increased growth inhibition and apoptosis in the lapatinib-treated cells (Figure 1)

Summary

Introduction

ErbB2 is a receptor tyrosine kinase (RTK) belonging to the epidermal growth factor receptor (EGFR) family, which is comprised of four members: EGFR/ErbB1, ErbB2/Her2/Neu, ErbB3, and ErbB4 [1, 2]. ErbB2 is the only EGFR family member that has no known binding ligand; the activation of ErbB2 depends largely on heterodimerization with other family members upon the binding of their cognate ligands. This interaction induces autophosphorylation of specific tyrosine residues within the catalytic kinase domain and triggers downstream cell signaling pathways [7]. Clinical implementation of therapeutic agents targeting ErbB2, including trastuzumab and lapatinib, has achieved remarkable benefits in patients with ErbB2-overexpressing breast cancer; the development of resistance to these novel agents is emerging as a significant clinical challenge

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Results

Conclusion