Abstract
Several selective CDK4/6 inhibitors are in clinical trials for non-small cell lung cancer (NSCLC). Palbociclib (PD0332991) is included in the phase II/III Lung-MAP trial for squamous cell lung carcinoma (LUSQ). We noted differential cellular activity between palbociclib and the structurally related ribociclib (LEE011) in LUSQ cells. Applying an unbiased mass spectrometry-based chemoproteomics approach in H157 cells and primary tumor samples, we here report distinct proteome-wide target profiles of these two drug candidates in LUSQ, which encompass novel protein and, for palbociclib only, lipid kinases. In addition to CDK4 and 6, we observed CDK9 as a potent target of both drugs. Palbociclib interacted with several kinases not targeted by ribociclib, such as casein kinase 2 and PIK3R4, which regulate autophagy. Furthermore, palbociclib engaged several lipid kinases, most notably, PIK3CD and PIP4K2A/B/C. Accordingly, we observed modulation of autophagy and inhibition of AKT signaling by palbociclib but not ribociclib.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2680-2686 |
| Number of pages | 7 |
| Journal | ACS chemical biology |
| Volume | 10 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 18 2015 |
Funding
This work was supported by the H. Lee Moffitt Cancer Center and Research Institute and the Moffitt Lung Cancer Center of Excellence. We furthermore wish to acknowledge the Moffitt Chemical Biology (Chemistry Unit) and Proteomics Core Facilities, which are supported by the National Cancer Institute (award no. P30-CA076292) as a Cancer Center Support Grant. The Proteomics Core is also supported by the U.S. Army Medical Research and Material Command (award no. W81XWH-08-2-0101) for a National Functional Genomics Center, the Moffitt Foundation, and the Bankhead-Coley Cancer Research program of the Florida Department of Health (09BE-04).
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
