PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer
| Autor: | M. Russillo, Sharat Singh, Joaquín Arribas, Sonia Rodríguez, Ludmila Prudkin, José Baselga, Pieter Johan Adam Eichhorn, M. Guzman, Benjamin Markman, Olga Rodriguez, Violeta Serra, Magui Gili, Neal Rosen, Maurizio Scaltriti, Sarat Chandarlapaty, Yasir H. Ibrahim, Josep-Lluís Parra |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
Cancer Research Receptor ErbB-3 Receptor ErbB-2 feedback Breast Neoplasms mTORC1 03 medical and health sciences 0302 clinical medicine HER2 Cell Line Tumor Genetics medicine PTEN Humans skin and connective tissue diseases Extracellular Signal-Regulated MAP Kinases Molecular Biology Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway 030304 developmental biology Phosphoinositide-3 Kinase Inhibitors 0303 health sciences biology TOR Serine-Threonine Kinases Cancer BEZ235 medicine.disease 3. Good health PI3K/mTOR ERK 030220 oncology & carcinogenesis Cancer research biology.protein Phosphorylation Original Article Female Tyrosine kinase Proto-Oncogene Proteins c-akt |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation. |
| Databáze: | OpenAIRE |
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