Thursday, October 3, 2013
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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
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
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
Broad's outlook in cancer, page 7).
Published online Oct. 3, 2013
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
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