NDLI: Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235.

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Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235.

Content Provider	Semantic Scholar
Author	Eichhorn, Pieter Johan Adam Gili, Magüi Scaltriti, Maurizio Serra, Violeta Guzmán, Marta Cristina Bonilla Nijkamp, Wouter Beijersbergen, Roderick Leonardus Valero, Vanesa Morante Seoane, Jose Miguel Bernards, René Baselga, José
Copyright Year	2008
Abstract	Small molecule inhibitors of HER2 are clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, we performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumor suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we show that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that phosphatidylinositol 3-kinase (PI3K)-induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance, which can be effectively reversed by NVP-BEZ235.
Starting Page	1
Ending Page	12
Page Count	12
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://cancerres.aacrjournals.org/content/canres/68/22/9221.full.pdf
PubMed reference number	19010894v1
Alternate Webpage(s)	https://doi.org/10.1158/0008-5472.CAN-08-1740
DOI	10.1158/0008-5472.can-08-1740
Journal	Cancer research
Volume Number	68
Issue Number	22
Language	English
Access Restriction	Open
Subject Keyword	1-Phosphatidylinositol 3-Kinase 1-Phosphatidylinositol 4-Kinase Deregulation Dual ERBB2 protein, human FRAP1 protein, human In Vitro [Publication Type] Mammary Neoplasms Modulator Device Component Mutation NVP BEZ235 Nevirapine Non-Small Cell Lung Carcinoma PIK3CA protein, human Phosphatidylinositide 3-Kinase Inhibitor Protein Tyrosine Kinase Protein-tyrosine kinase inhibitor RNA Tumor Suppressor Genes lapatinib trastuzumab
Content Type	Text
Resource Type	Article

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