MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma

Oral Oncol. 2019 Nov;98:147-155. doi: 10.1016/j.oraloncology.2019.09.005. Epub 2019 Oct 10.

Abstract

Objective: There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development.We aim to develop MYB-activated models for testing new therapeutic agents.

Materials and methods: We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+/-/Arf+/- mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors.

Results: We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using shRNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like mRNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models.

Conclusions: We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

Keywords: Adenoid cystic cancer; B-cell leukemia; MYB gene; Peptidomimetic inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Adenoid Cystic / drug therapy
  • Carcinoma, Adenoid Cystic / genetics*
  • Carcinoma, Adenoid Cystic / metabolism
  • Carcinoma, Adenoid Cystic / pathology
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Disease Models, Animal
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Proteomics / methods
  • Proto-Oncogene Proteins c-myb / genetics*
  • Proto-Oncogene Proteins c-myb / metabolism
  • Sequence Analysis, RNA
  • Transcriptional Activation*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • MYB protein, human
  • Proto-Oncogene Proteins c-myb