This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hann, C. L. Articles by Rudin, C. M. Search for Related Content PubMed PubMed Citation Articles by Hann, C. L. Articles by Rudin, C. M.

Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: Charles M. Rudin, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, David H. Koch Cancer Research Building, Room 544, 1550 Orleans Street, Baltimore MD 21231. Phone: 410-502-0678; Fax: 410-502-0677; E-mail: rudin{at}jhmi.edu.

Key Words: Bcl-2 • small cell lung cancer • ABT-737 • primary xenograft • heterotransplant

Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. We compared primary SCLC xenografts prepared from de novo human tumors with standard cell line–based xenografts in the evaluation of a novel and highly potent small molecule inhibitor of Bcl-2, ABT-737. ABT-737 induced dramatic regressions in tumors derived from some SCLC cell lines. In contrast, only one of three primary xenograft SCLC tumors showed significant growth inhibition with ABT-737. Explanations for this apparent dichotomy may include relatively low expression of Bcl-2 in the primary xenografts or inherent differences in the model systems. The addition of etoposide to ABT-737 in the primary xenografts resulted in significant decreases in tumor growth, underscoring the clinical potential of ABT-737 in combination therapy. To identify factors that may contribute to resistance to ABT-737 and related inhibitors, we isolated resistant derivatives of an initially sensitive cell line–based xenograft. Acquired resistance in this model was associated with decreases in the expression of the primary target Bcl-2, of proapoptotic partners of Bcl-2 (Bax and Bim), and of Bcl-2:Bim heterodimers. Expression profiling reveals 85 candidate genes demonstrating consistent changes in gene expression with acquired resistance. Taken together, these data have specific implications for the clinical development of Bcl-2 inhibitors for SCLC and broader implications for the testing of novel anticancer strategies in relevant preclinical models. [Cancer Res 2008;68(7):2321–8]

This article has been cited by other articles:

				S. Chen, Y. Dai, X.-Y. Pei, and S. Grant Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1 Mol. Cell. Biol., December 1, 2009; 29(23): 6149 - 6169. [Abstract] [Full Text] [PDF]

				K. W. Kim, L. Moretti, L. R. Mitchell, D. K. Jung, and B. Lu Combined Bcl-2/Mammalian Target of Rapamycin Inhibition Leads to Enhanced Radiosensitization via Induction of Apoptosis and Autophagy in Non-Small Cell Lung Tumor Xenograft Model Clin. Cancer Res., October 1, 2009; 15(19): 6096 - 6105. [Abstract] [Full Text] [PDF]

				J. L. Hurwitz, F. McCoy, P. Scullin, and D. A. Fennell New Advances in the Second-Line Treatment of Small Cell Lung Cancer Oncologist, October 1, 2009; 14(10): 986 - 994. [Abstract] [Full Text] [PDF]

				V. C. Daniel, L. Marchionni, J. S. Hierman, J. T. Rhodes, W. L. Devereux, C. M. Rudin, R. Yung, G. Parmigiani, M. Dorsch, C. D. Peacock, et al. A Primary Xenograft Model of Small-Cell Lung Cancer Reveals Irreversible Changes in Gene Expression Imposed by Culture In vitro Cancer Res., April 15, 2009; 69(8): 3364 - 3373. [Abstract] [Full Text] [PDF]

				P. Hauck, B. H. Chao, J. Litz, and G. W. Krystal Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737 Mol. Cancer Ther., April 1, 2009; 8(4): 883 - 892. [Abstract] [Full Text] [PDF]

				Z. Wang, A. S. Azmi, A. Ahmad, S. Banerjee, S. Wang, F. H. Sarkar, and R. M. Mohammad TW-37, a Small-Molecule Inhibitor of Bcl-2, Inhibits Cell Growth and Induces Apoptosis in Pancreatic Cancer: Involvement of Notch-1 Signaling Pathway Cancer Res., April 1, 2009; 69(7): 2757 - 2765. [Abstract] [Full Text] [PDF]

				T. Jiang, B. J. Collins, N. Jin, D. N. Watkins, M. V. Brock, W. Matsui, B. D. Nelkin, and D. W. Ball Achaete-Scute Complex Homologue 1 Regulates Tumor-Initiating Capacity in Human Small Cell Lung Cancer Cancer Res., February 1, 2009; 69(3): 845 - 854. [Abstract] [Full Text] [PDF]