Abstract B144: NVP-BEZ235, a dual inhibitor of PI3K and mTOR, induces MAPK phosphorylation in HER2-positive cells

• Published in: Molecular cancer therapeutics 2009-12, Vol.8 (12_Supplement), p.B144-B144
• Main Authors: Elizalde, Violeta Serra, Eichhorn, Pieter JA, Scaltriti, Maurizio, Prudkin, Ludmila, Rodriguez, Olga, Guzman, Marta, Baselga, José
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-B144

The PI3K pathway is highly deregulated in human cancer with the most common alterations being amplification of the receptor tyrosine kinases (RTKs) EGFR and HER2 and mutations in PI3K itself or inactivation of the tumor suppressor PTEN. Thus, the rationale exists to develop therapeutic agents targeting the PI3K/AKT pathway. Several small molecule inhibitors targeting PI3K, AKT and mTOR are now in clinical trials. However, these novel compounds may interfere with regulatory feedback loops. One such example involves the activation of AKT following rapamycin analogues treatment, such as everolimus, an allosteric mTOR inhibitor. Blocking mTOR signaling also alters the regulation of other signaling pathways, like the MAPK cascade. The aim of this study was to investigate the mechanism/s by which inhibition of the PI3K pathway leads to activation of MAPK kinase signaling in breast cancer cell lines and its relevance in tumor treatment. We have observed an increased MAPK phosphorylation in HER2 positive BT474, SKBR-3, MDA-361 and MCF-7HER2 cells when treated with NVP-BEZ235, a dual inhibitor of both mTOR and p110, the catalytic component of PI3K. The increase of P-MAPK was observed by western blot and correlated with hyperphosphorylation of several RTKs. PD325901, a MEK1/2 inhibitor, or lapatinib, a HER1/2 tyrosine kinase inhibitor, reverted the NVP-BEZ235-induced MAPK phosphorylation. On the other hand, NVP-AEW541, an IGFR-1 tyrosine kinase inhibitor, did not prevent NVP-BEZ235-dependent HER2 phosphorylation and downstream MAPK activation. Activation of MAPK upon administration of NVP-BEZ235 was also observed in vivo. We are currently investigating the possible involvement of known regulatory feedback loops as well as the individual RTK contribution. Activation of parallel pathways in a condition of PI3K inhibition may reduce potential benefits of these anti-cancer treatments. For this reason, we propose the combination of an anti-HER2 therapy together with PI3K inhibitors for the treatment of HER2 positive tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B144.