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Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer
journal contribution
posted on 2015-12-18, 00:00 authored by Natalia
J. Sumi, Brent M. Kuenzi, Claire
E. Knezevic, Lily L. Remsing Rix, Uwe RixSeveral 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.