Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition.

Abstract

Non-small cell lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Such cancers are "addicted" to EGFR, and treatment with a TKI invariably leads to down-regulation of the PI3K-AKT-mTOR and MEK-ERK signaling pathways, resulting in apoptosis. Using a dual PI3K-mTOR inhibitor, NVP-BEZ235, we evaluated whether PI3K-mTOR inhibition alone induced apoptosis in these cancers. In contrast to HER2-amplified breast cancers, we found that PI3K-mTOR inhibition did not promote substantial apoptosis in the EGFR mutant lung cancers. However, blocking both PI3K-mTOR and MEK simultaneously led to apoptosis to similar levels as the EGFR TKIs, suggesting that down-regulation of these pathways may account for much of the apoptosis promoted by EGFR inhibition. In EGFR mutant lung cancers, down-regulation of both intracellular pathways converged on the BH3 family of proteins regulating apoptosis. PI3K inhibition led to down-regulation of Mcl-1, and MEK inhibition led to up-regulation of BIM. In fact, down-regulation of Mcl-1 by siRNA was sufficient to sensitize these cancers to single-agent MEK inhibitors. Surprisingly, an AKT inhibitor did not decrease Mcl-1 levels, and when combined with MEK inhibitors, failed to induce apoptosis. Importantly, we observed that the combination of PI3K-mTOR and MEK inhibitors effectively shrunk tumors in a transgenic and xenograft model of EGFR T790M-L858R cancers. These data indicate simultaneous inhibition of PI3K-mTOR and MEK signaling is an effective strategy for treating EGFR mutant lung cancers, including those with acquired resistance to EGFR TKIs.

• Authors: Anthony C Faber, Danan Li, Youngchul Song, Mei-Chih Liang, Beow Y Yeap, Roderick T Bronson, Eugene Lifshits, Zhao Chen, Sauveur-Michel Maira, Carlos García-Echeverría, Kwok-Kin Wong, Jeffrey A Engelman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 46 Pg. 19503-8 (Nov 17 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19850869 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Quinazolines
• Quinolines
• Erlotinib Hydrochloride
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• TOR Serine-Threonine Kinases
• MAP Kinase Kinase Kinases
• dactolisib
• Gefitinib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis
• Breast Neoplasms (drug therapy, genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• ErbB Receptors (genetics)
• Erlotinib Hydrochloride
• Female
• Gefitinib
• Humans
• Imidazoles (pharmacology)
• Lung Neoplasms (drug therapy, genetics)
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Mice
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (therapeutic use)
• Protein Kinases (metabolism)
• Quinazolines (pharmacology)
• Quinolines (pharmacology)
• Receptor, ErbB-2 (genetics)
• TOR Serine-Threonine Kinases
• Xenograft Model Antitumor Assays