Chemoproteomics Reveals Novel Protein and Lipid Kinase
Targets of Clinical CDK4/6 Inhibitors in Lung Cancer
Natalia
J. Sumi
Brent M. Kuenzi
Claire
E. Knezevic
Lily L. Remsing Rix
Uwe Rix
10.1021/acschembio.5b00368.s001
https://acs.figshare.com/articles/journal_contribution/Chemoproteomics_Reveals_Novel_Protein_and_Lipid_Kinase_Targets_of_Clinical_CDK4_6_Inhibitors_in_Lung_Cancer/2097025
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.
2015-12-18 00:00:00
3CD
PIK
PIP
LEE
casein kinase 2
3R
autophagy
lipid kinases
Palbociclib
PD
ribociclib
AKT
cell lung carcinoma
LUSQ
NSCLC
H 157 cells
CDK
palbociclib
II
4K