Activity-Based Proteomics Reveals Heterogeneous Kinome and ATP-Binding Proteome Responses to MEK Inhibition in KRAS Mutant Lung Cancer.
One way cancer cells can escape from targeted agents is through their ability to evade drug effects by rapidly rewiring signaling networks. Many protein classes, such as kinases and metabolic enzymes, are regulated by ATP binding and hydrolysis. We hypothesized that a system-level profiling of drug-induced alterations in ATP-binding proteomes could offer novel insights into adaptive responses. Here, we mapped global ATP-binding proteomes perturbed by two clinical MEK inhibitors, AZD6244 and MEK162, in KRAS mutant lung cancer cells as a model system harnessing a desthiobiotin-ATP probe coupled with LC-MS/MS. We observed strikingly unique ATP-binding proteome responses to MEK inhibition, which revealed heterogeneous drug-induced pathway signatures in each cell line. We also identified diverse kinome responses, indicating each cell adapts to MEK inhibition in unique ways. Despite the heterogeneity of kinome responses, decreased probe labeling of mitotic kinases and an increase of kinases linked to autophagy were identified to be common responses. Taken together, our study revealed a diversity of adaptive ATP-binding proteome and kinome responses to MEK inhibition in KRAS mutant lung cancer cells, and our study further demonstrated the utility of our approach to identify potential candidates of targetable ATP-binding enzymes involved in adaptive resistance and to develop rational drug combinations.
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Jae-Young
JY
Kim
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Paul A
0000-0003-0882-308X
PA
Stewart
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Adam L
0000-0001-5275-4195
AL
Borne
Proteomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Bin
B
Fang
Cancer Informatics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Eric A
EA
Welsh
Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Yian Ann
YA
Chen
Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Steven A
SA
Eschrich
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
John M
0000-0002-3818-1762
JM
Koomen
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Eric B
EB
Haura
KRAS mutant lung cancer; LC-MS/MS; MEK inhibitor; adaptive resistance; desthiobiotin-ATP probe