The Bcl-2 family proteins are key regulators of apoptosis, whose overexpression has been identified in cancer and associated with chemoresistance. A small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w (ABT-737) has been discovered and shown to improve survival, cause regression of established tumours, and produce cures in mouse models of small cell lung carcinomas (SCLC). The identification of specific patient populations responsive to Bcl-2 family inhibitors would greatly enhance their clinical utility.Using 23 small cell lung cancer lines with a broad range of sensitivity to ABT-737, genome-wide comparative genomic hybridization (CGH) studies were performed to identify regions of genetic aberrations that are associated with efficacy. Using the Affymetrix 100K SNP genotyping arrays and an in-house bioinformatics tool, we identified gene copy number alterations that correlate with the sensitivity of the cell lines to ABT-737. A long region on the chromosome 18q was amplified in the sensitive, but not in the resistant lines. Among other genes, Bcl-2 was found to be moderately amplified in cell lines that were highly sensitive to ABT-737. We explored the clinical relevance of the 18q amplification by analyzing previously published CGH datasets for SCLC tumours and by examining the Bcl-2 copy number on SCLC tissue microarrays using FISH. The amplification was detected in a significant fraction of tumours, thus raising the possibility of patient stratification for the treatment with Bcl-2 inhibitors. This study illustrates our approach to early discovery of patient stratification biomarkers for oncology drug candidates.

[First AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development, Sep 12-15, 2006]