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Cell Signal. 2020 Jan 3:109525. doi: 10.1016/j.cellsig.2020.109525. [Epub ahead of print]
Enhanced signaling via ERBB3/PI3K plays a compensatory survival role in pancreatic tumor cells exposed to [neratinib + valproate].
Dent P1, Booth L2, Poklepovic A3, Hoff DV4, Hancock JF5.
1
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, United States. Electronic address: paul.dent@vcuhealth.org.
2
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298-0035, United States.
3
Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0035, United States.
4
Translational Genomics Research Institute (TGEN), Phoenix, AZ 85004, United States.
5
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX 77030, United States.
The ERBB1/2/4 inhibitor neratinib causes plasma membrane-associated K-RAS to mislocalize into intracellular vesicles; this effect is enhanced by HDAC inhibitors and the combination of [neratinib + sodium valproate] is now a phase I trial (NCT03919292). The present studies were performed to understand resistance mechanisms that evolve following [neratinib + valproate] exposure. Exposure of pancreatic tumor cells to [neratinib + sodium valproate] initially reduced the expression and phosphorylation of ERBB family receptors, c-MET and c-KIT. Following a 24?h drug exposure and a further 24?h culture in drug free conditions, the effects on c-MET, c-KIT and most ERBB family receptors had returned to near baseline levels. However, the expression and phosphorylation of ERBB3 were increased which was associated with elevated AKT T308 phosphorylation. Knock down of ERBB3 significantly enhanced [neratinib + valproate] lethality, which was associated with greater inactivation of AKT, mTOR, p70 S6K and ERK1/2. The PI3Ka/d inhibitor copanlisib also significantly enhanced killing after [neratinib + valproate] exposure. Copanlisib enhanced [neratinib + valproate] lethality via autophagosome formation and autophagic flux. Our data argue for further in vivo exploration as to whether copanlisib can be safely combined with [neratinib + valproate]. |
