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[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1

Laurence Booth1, Jane L Roberts1, Rumeesa Rais1

  • 1Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.

Oncotarget
|February 22, 2018
PubMed

Insights

Neratinib and valproate combination therapy slows 4T1 mammary tumor growth by altering tumor biology. This drug combination enhances immune cell infiltration and increases sensitivity to immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Neratinib, an ERBB1/2/4 inhibitor, reduces ERBB1/2/4 and RAS proteins via autophagic degradation.
  • Previous studies showed neratinib and valproate synergistically suppress 4T1 mammary tumor growth.
  • The impact of this drug combination on 4T1 tumor cell biology in vivo was not fully understood.

Purpose of the Study:

  • To investigate the biological alterations in 4T1 mammary tumors following exposure to the [neratinib + valproate] combination.
  • To determine the long-term effects of this drug combination on tumor growth, immune microenvironment, and gene expression.
  • To assess the potential of this combination to enhance immunotherapy response.

Main Methods:

  • 4T1 mammary tumors in mice were exposed to [neratinib + valproate] for three days.
  • Tumor growth, protein expression (ERBB1, RAS, IDO-1, ODC, MHCA), immune cell infiltration (CD8+, NK, M1/M2 macrophages), and histone deacetylase (HDAC) expression were analyzed.
  • In vitro studies assessed the effect of the drug combination on HDAC expression in 4T1 cells.

Main Results:

  • Two weeks post-treatment, tumors showed reduced ERBB1, K-RAS, N-RAS, IDO-1, and ODC expression, with increased Class I MHCA.
  • Previously treated tumors exhibited slower growth and increased infiltration of CD8+ T cells, activated NK cells, and M1 macrophages.
  • In vivo, neratinib + valproate permanently reduced HDACs 1-3, 6, and 10 expression, while in vitro studies showed variable reduction in HDACs 1-11.
  • Combined knockdown of specific HDACs mimicked the effects on IDO-1, ODC, and MHCA expression.

Conclusions:

  • The [neratinib + valproate] combination therapy induces lasting biological changes in 4T1 tumors, leading to slower growth.
  • This combination enhances anti-tumor immunity by modulating the tumor microenvironment and increasing immune cell infiltration.
  • Neratinib and valproate treatment sensitizes 4T1 tumors to checkpoint immunotherapy, offering a potential therapeutic strategy.
Keywords:
autophagyneratinibreceptor tyrosine kinasevalproate

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