Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ErbB2-overexpressing breast cancers.

Full Abstract

Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer.

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Author information

Author/s: Xia, Wenle (W); Husain, Intisar (I); Liu, Leihua (L); Bacus, Sarah (S); Saini, Shermini (S); Spohn, Janice (J); Pry, Karen (K); Westlund, Ron (R); Stein, Steven H (SH); Spector, Neil L (NL);

Affiliation: Department of Oncology Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Journal and publication information

Publication Type: Journal Article

Journal: Cancer research (Cancer Res), published in United States. (Language: eng)

Reference: 2007-Feb; vol 67 (issue 3) : pp 1170-5

Dates: Created 2007/02/06; Completed 2007/03/01;

PMID: 17283152, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

1-Phosphatidylinositol 3-Kinase - metabolism
Antineoplastic Agents - pharmacology
Apoptosis - drug effects; physiology
Breast Neoplasms - drug therapy; enzymology; genetics
Cell Line, Tumor
Humans

PTEN Phosphohydrolase - deficiency; genetics
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
Quinazolines - pharmacology
Receptor, erbB-2 - antagonists & inhibitors; biosynthesis; metabolism
Signal Transduction - drug effects

Associated Chemicals: Antineoplastic Agents (0) ; Quinazolines (0) ; lapatinib (0) ; Receptor, erbB-2 (EC 2.7.1.112) ; 1-Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.1.37) ; PTEN protein, human (EC 3.1.3.48) ; PTEN Phosphohydrolase (EC 3.1.3.67)

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