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.