RT Journal Article
SR Electronic
T1 Target identification in small cell lung cancer via integrated phenotypic screening and activity-based protein profiling
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.0444.2015
DO 10.1158/1535-7163.MCT-15-0444
A1 Li, Jiannong
A1 Fang, Bin
A1 Kinose, Fumi
A1 Bai, Yun
A1 Kim, Jae-Young
A1 Chen, Yian Ann
A1 Rix, Uwe
A1 Koomen, John M.
A1 Haura, Eric B
YR 2016
UL http://mct.aacrjournals.org/content/early/2016/01/15/1535-7163.MCT-15-0444.abstract
AB To overcome hurdles in identifying key kinases in small cell lung cancer (SCLC), we integrated a target-agnostic phenotypic screen of kinase inhibitors with target identification using activity-based protein profiling (ABPP) in which a desthiobiotin-ATP probe was used. We screened 21 SCLC cell lines with known c-MYC amplification status for alterations in viability using a chemical library of 235 small molecule kinase inhibitors. One screen hit compound was interrogated with ABPP, and through this approach we re-identified aurora kinase B as a critical kinase in MYC-amplified SCLC cells. We next extended the platform to a second compound that had activity in SCLC cell lines lacking c-MYC amplification and identified TANK-binding kinase 1 (TBK1), a kinase that affects cell viability, polo-like kinase-1 signaling, G2/M arrest, and apoptosis in SCLC cells lacking MYC amplification. These results demonstrate that phenotypic screening combined with activity-based protein profiling can identify key disease drivers, suggesting that this approach, which combines new chemical probes and disease cell screens, has the potential to identify other important targets in other cancer types.