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b-Catenin (CTNNB1);
B cell lymphoma 2 (BCL-2; BCL2); AXIN1; casein kinase 1a (CSNK1A1; CKI-a)

In vitro studies suggest mutations in CTNNB1 or in genes regulating its degradation may predict tumor responses to BCL2 inhibitors. In a screen of human colorectal, endometrial, gastric, liver and lung cancer cell lines treated with small molecule inhibitors, genomic profiling identified correlations between activating mutations in CTNNB1 and sensitivity to the BCL2 inhibitor navitoclax. Genomic profiling of the treated cancer cell lines also identified correlations between sensitivity to navitoclax and loss-of-function mutations in AXIN1 and CSNK1A1, which affect CTNNB1 degradation. Ongoing work includes testing navitoclax in mice bearing CTNNB1-mutant xenograft tumors.
AbbVie Inc. and Roche's Genentech Inc. unit have navitoclax (ABT-263; RG7433), a pan-BCL2 inhibitor, in Phase I/II testing to treat small cell lung cancer and Phase I testing to treat solid tumors.
Roche and AbbVie have ABT-199 (RG7601; GDC-0199), a small molecule inhibitor of BCL2, in Phase II testing to treat chronic lymphocytic leukemia (CLL).
Ascentage Pharma Group Corp. Ltd. and 3SBio Inc. have a pan-BCL2 inhibitor in Phase II testing to treat non-small cell lung cancer (NSCLC; see The Broad's outlook in cancer, page 7).

SciBX 6(38); doi:10.1038/scibx.2013.1057
Published online Oct. 3, 2013

Unpatented; unlicensed

Basu, A. et al. Cell; published online Aug. 29, 2013;
Contact: Stuart L. Schreiber, Broad Institute of MIT and Harvard, Cambridge, Mass.

Contact: Alykhan F. Shamji, same affiliation as above

Contact: Paul A. Clemons, same affiliation as above