Phenotype-based screens with conformation-specific inhibitors reveal p38 gamma and delta as targets for HCC polypharmacology

Jia Xin Yu, Amanda J. Craig, Mary E. Duffy, Carlos Villacorta-Martin, Veronica Miguela, Marina Ruiz de Galarreta, Alexander P. Scopton, Lisa Silber, Andres Y. Maldonado, Alexander Rialdi, Ernesto Guccione, Amaia Lujambio, Augusto Villanueva, Arvin C. Dar

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Pages (from-to)1506-1519
Number of pages14
JournalMolecular Cancer Therapeutics
Issue number9
StatePublished - 2019


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