Abstract
Abstract Small cell lung cancer (SCLC) accounts for approximately 13% of lung cancer cases, and current treatment options are limited to radiation and/or chemotherapy, which frequently lead to drug resistance. Recently, multiple SCLC cell lines have been found to be responsive to the Bcl-2/Bcl-xL inhibitor, ABT-737, both in vitro and in vivo. Clinical trials of the related orally-bioavailable compound ABT-263 have shown promising activity in SCLC patients. However, a subset of SCLC cell lines that express Mcl-1, another anti-apoptotic protein, are resistant to ABT-737. Therefore, drugs targeting Mcl-1 may be particularly useful in this disease. Here, we have investigated dependence of a panel of SCLC cell lines on Mcl-1 for survival. A subset of Mcl-1-expressing SCLC cell lines, including NCI-H82, NCI-N417 and SHP-77, demonstrate apoptosis upon Mcl-1 knockdown. However, other SCLC cell lines, including NCI-H69, NCI-H196 and SW1271, are not responsive to Mcl-1 knockdown. In addition, the dependence of SCLC cell lines on Mcl-1 for survival can be predicted by BH3 profiling, a methodology that measures dependence of a cell on a variety of anti-apoptotic proteins. We have also investigated the efficacy of Flavopiridol, a potent inhibitor of the transcriptional cyclin-dependent kinase (cdk)9, against the panel of SCLC cell lines. Flavopiridol acutely down-regulates Mcl-1 expression in all SCLC cell lines tested; however, only Mcl-1-dependent cells, including NCI-H82, NCI-N417 and SHP-77, undergo abrupt apoptosis. In contrast, cells that were not found to be Mcl-1 dependent are not effectively killed by Flavopiridol. We have further investigated the activity of Flavopiridol against Mcl-1-dependent SCLC in vivo utilizing nude mice bearing NCI-H82 xenografts. Flavopiridol treatment results in substantial tumor growth inhibition in this aggressive and chemotherapy-refractory model. To potentially stratify patients who would be predicted to be responsive to Flavopiridol treatment, we have performed MCL-1 gene fluorescence in situ hybridization in SCLC cell lines and deidentified patient specimens. MCL-1 gene copy number gains exist in both patient and cell line samples, and copy number gain of MCL-1 or MYC in cell lines correlates with Mcl-1 dependence. Strategies for targeting MCL-1 and MYC copy number gains will be discussed further. Finally, we have demonstrated that the combination of Flavopiridol and ABT-737 significantly reduces viability in Mcl-1-independent SW1271 cells compared to treatment with either drug alone. Taken together, our studies suggest that Flavopiridol-mediated cdk9 inhibition may effectively target Mcl-1-dependent SCLCs, including those resistant to Bcl-2/Bcl-xL inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2016. doi:1538-7445.AM2012-2016
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