Abstract 575: A subset of small cell lung cancer (SCLC) cell lines are Mcl-1-dependent and undergo apoptosis in response to Flavopiridol-mediated inhibition of cyclin-dependent kinase (cdk) 9

Abstract

Abstract Small cell lung cancer (SCLC) accounts for approximately 13% of lung cancer cases. Although SCLC is initially a chemosensitive disease, the development of resistance is a major obstacle. Recently, multiple SCLC cell lines have been found to be responsive to a Bcl-2/Bcl-xL inhibitor, ABT-737, both in vitro and in vivo (Oltersdorf T et al. Nature. 2005 Jun 2; 435(7042): 677-81). Clinical trials of the related orally-available 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 treatment. Furthermore, SCLC lines have elevated expression of Mcl-1 when they become resistant to ABT-737 (Tahir SK et al. Cancer Res. 2007 Feb 1; 67(3): 1176-83). 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, using Mcl-1 knockdown achieved by lentiviral-based shRNA technology. Several SCLC cell lines expressing Mcl-1, including NCI-H82 and SHP77 cells, demonstrate apoptosis by TUNEL assay and reduced viability by MTS assay in response to Mcl-1 depletion. However, other SCLC cell lines, including NCI-H69 and SW1271, are not responsive to Mcl-1 knockdown. We have also investigated the efficacy of Flavopiridol, a potent inhibitor of cdk9, against a panel of SCLC cell lines. Flavopiridol acutely down-regulates Mcl-1 expression in NCI-H82, SHP77, H69 and SW1271 cells. Mcl-1-dependent cell lines, including H82 and SHP77, undergo abrupt apoptosis in response to Flavopiridol. In contrast, H69 and SW1271 cells, which were not found to be Mcl-1-dependent, were not effectively killed by Flavopiridol. These data suggest that Mcl-1-dependent SCLC cells may be particularly sensitive to Flavopiridol treatment to overcome ABT-737 resistance. Finally, we have demonstrated that the combination of Flavopiridol and ABT-737 can synergistically kill both Mcl-1-dependent and -independent SCLC cells, with significantly reduced viability in SHP77 and SW1271 cells compared to treatment with either drug alone. Taken together, our studies suggest 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 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 575.