Journal
MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 9, Pages 1506-1519Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-18-0571
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Funding
- NIH [NCI F31CA210639, T32CA078207, T32GM062754, RO1CA227636]
- Damon RunyonRachleff Foundation [DRR28-15]
- Tisch Cancer Institute [P30 CA196521]
- Tisch Cancer Institute Development Funding Award
- U.S. Department of Defense [CA150272P2, CA150178, CA150272P3]
- Damon Runyon-Rachleff Foundation [DR52-18]
- Fundacion Alfonso Martin Escudero Fellowship
- Damon Runyon-Rachleff Innovation Award [DR52-18]
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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 p38 delta/gamma activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6 -> p38 -> qUF2 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 MCC and an AD80 inhibition signature as identifying those patients with best clinical outcomes.
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