Target Identification in Small Cell Lung Cancer via Integrated Phenotypic Screening and Activity-Based Protein Profiling

Molecular Cancer Therapeutics
Jiannong LiEric B Haura

Abstract

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 reidentified 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, 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 ABPP 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. Mol Cancer Ther; 15(2); 334-42. ©2016 AACR.

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Citations

Aug 12, 2016·The Lancet Oncology·Wan-Ling TanDaniel S W Tan
Jul 19, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·You-Guang ZhengMin Ji
Dec 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Quentin T L PasquerSascha Hoogendoorn
Dec 10, 2020·International Journal of Molecular Sciences·Kyoung-Min ChoiJae-Young Kim
Feb 13, 2021·Cell Chemical Biology·Louis P ConwayChristopher G Parker
Sep 28, 2020·Pharmacology & Therapeutics·Anutthaman ParthasarathyKarunakaran Kalesh
Nov 23, 2017·Journal of Proteome Research·Melissa A HoffmanJohn M Koomen
Jul 1, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Jeffrey A KernAik-Choon Tan

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