TY - JOUR
T1 - Phenotype-based screens with conformation-specific inhibitors reveal p38 gamma and delta as targets for HCC polypharmacology
AU - Yu, Jia Xin
AU - Craig, Amanda J.
AU - Duffy, Mary E.
AU - Villacorta-Martin, Carlos
AU - Miguela, Veronica
AU - de Galarreta, Marina Ruiz
AU - Scopton, Alexander P.
AU - Silber, Lisa
AU - Maldonado, Andres Y.
AU - Rialdi, Alexander
AU - Guccione, Ernesto
AU - Lujambio, Amaia
AU - Villanueva, Augusto
AU - Dar, Arvin C.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38d/g activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6!p38!ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.
AB - The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38d/g activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6!p38!ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.
UR - http://www.scopus.com/inward/record.url?scp=85071783654&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-18-0571
DO - 10.1158/1535-7163.MCT-18-0571
M3 - Article
C2 - 31213506
AN - SCOPUS:85071783654
SN - 1535-7163
VL - 18
SP - 1506
EP - 1519
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 9
ER -