[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration
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Laurence Booth1, Jane L. Roberts1, Rumeesa Rais1, John Kirkwood4, Francesca Avogadri-Connors3, Richard E. Cutler Jr.3, Alshad S. Lalani3, Andrew Poklepovic2 and Paul Dent1
1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA
2Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
3Puma Biotechnology Inc., Los Angeles, CA 90024, USA
4University of Pittsburgh Cancer Institute Melanoma and Skin Cancer Program, Hillman Cancer Research Pavilion Laboratory L1.32c, Pittsburgh, PA 15232, USA
Paul Dent, email: [email protected]
Keywords: autophagy; receptor tyrosine kinase; neratinib; valproate
Received: November 22, 2017 Accepted: December 12, 2017 Published: December 26, 2017
The irreversible ERBB1/2/4 inhibitor neratinib has been shown in vitro to rapidly reduce the expression of ERBB1/2/4 and RAS proteins via autophagic/lysosomal degradation. We have recently demonstrated that neratinib and valproate interact to suppress the growth of 4T1 mammary tumors but had not defined whether the [neratinib + valproate] drug combination, in a mouse, had altered the biology of the 4T1 cells. Exposure of 4T1 mammary tumors to [neratinib + valproate] for three days resulted, two weeks later, in tumors that expressed less ERBB1, K-RAS, N-RAS, indoleamine-pyrrole 2,3-dioxygenase (IDO-1), ornithine decarboxylase (ODC) and had increased Class I MHCA expression. Tumors previously exposed to [neratinib + valproate] grew more slowly than those exposed to vehicle control and contained more CD8+ cells and activated NK cells. M1 but not M2 macrophage infiltration was significantly enhanced by the drug combination. In vitro exposure of 4T1 tumor cells to [neratinib + valproate] variably reduced the expression of histone deacetylases 1-11. In vivo, prior exposure of tumors to [neratinib + valproate] permanently reduced the expression of HDACs 1-3, 6 and 10. Combined knock down of HDACs 1/2/3 or of 3/10 rapidly reduced the expression IDO-1, and ODC and increased the expression of MHCA. H&E staining of normal tissues at animal nadir revealed no obvious cyto-architectural differences between control and drug-treated animals. We conclude that [neratinib + valproate] evolves 4T1 tumors to grow more slowly and to be more sensitive to checkpoint immunotherapy antibodies.
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