Abstract 5438: A novel therapeutic combination with synergistic antitumor activity in colon cancer: The dual tyrosine kinase inhibitor lapatinib and the histone deacetylase inhibitor LBH589
| Autor: | Melissa J. LaBonte, Robert D. Ladner, Heinz-Josef Lenz, Peter M. Wilson, Anthony B. El-Khoueiry |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
biology medicine.drug_class Colorectal cancer business.industry Histone deacetylase inhibitor Cancer Pharmacology Lapatinib medicine.disease medicine.disease_cause Tyrosine-kinase inhibitor chemistry.chemical_compound Oncology chemistry Panobinostat medicine biology.protein Epidermal growth factor receptor KRAS business medicine.drug |
| Zdroj: | Cancer Research. 70:5438-5438 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States. Effective treatment is hindered by the high incidence of drug resistance and tumor recurrence, resulting in the need to identify and exploit novel therapeutic targets and drug combinations to improve clinical efficacy. The epidermal growth factor receptor (EGFR) has been implicated in colon cancer growth, progression and chemoresistance and inhibition of EGFR has therefore become an efficacious drug target. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER-2 and suppressing oncogenic signaling through the RAS-RAF-MEK-ERK and PI3K/AKT pathways. Histone deacetylase inhibitors (HDACi) are a novel class of agents demonstrating promising activity against colon cancer cells through the hyper-acetylation of histone and non-histone proteins resulting in cell cycle arrest and apoptosis. HDACi are also reported to disrupt HSP90 function, inducing the degradation of EGFR-pathway client proteins (e.g. EGFR, HER-2, BRAF). This study sought to evaluate the therapeutic potential of lapatinib in combination with the HDACi LBH589 (Panobinostat) in a panel of eight colon cancer cell lines with varying EGFR/HER-2 expression and KRAS mutational status. EGFR and HER-2 mRNA and protein expression levels were determined by quantitative PCR and Western blot. Concentration-dependent antiproliferative effects of both lapatinib and LBH589 were observed in vitro (lapatinib range 7.6-15.8 μM; LBH589 range 7.2-30 nM) using the MTS assay. The combination of LBH589 and lapatinib interacted synergistically to inhibit both cell proliferation and colony formation in all colon cancer cell lines tested. Combination treatment resulted in decreased signaling through both the PI3K and MAPK pathways as determined by decreased levels of phospho-AKT and phospho-p44/42 MAPK. Co-treatment with lapatinib and LBH589 also resulted in the rapid induction of apoptosis as early as 18 h post-treatment as determined by flow cytometry and Western blot analysis of apoptotic factors including cleaved caspase-8 and PARP. These in vitro observations were extended to a LoVo colon cancer xenograft model where combination treatment resulted in greater antitumor activity than either lapatinib or LBH589 alone, with no apparent increase in toxicity. Together these data provide scientific rationale warranting further investigation of HDACi in combination with EGFR and HER-2-targeted therapies for the treatment of colorectal cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5438. |
| Databáze: | OpenAIRE |
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