Selective ERBB2 and BCL2 Inhibition is Synergistic for Mitochondrial-mediated Apoptosis in MDS and AML cells.

Journal Article (Journal Article)

The ERBB2 proto-oncogene is associated with an aggressive phenotype in breast cancer. Its role in hematologic malignancies is incompletely defined, in part because ERBB2 is not readily detected on the surface of cancer cells. We demonstrate that truncated ERBB2, which lacks the extracellular domain, is overexpressed on primary CD34+ myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells compared to healthy hematopoietic cells. This overexpression of ERBB2 is associated with aberrant, oncogenic signaling with autophosphorylation of multiple tyrosine sites. Like in breast cancers, ERBB2 can exist as truncated isoforms p95ERBB2 and p110ERBB2 in MDS and AML. Neutralization of ERBB2 signaling with ERBB2 tyrosine kinase inhibitors (i.e., lapatinib, afatinib, and neratinib) increases apoptotic cell death and reduces human engraftment of MDS cells in mice at 21 weeks post-transplantation. Inhibition of ERBB2 modulates the expression of multiple pro- and anti-apoptotic mitochondrial proteins, including B-cell lymphoma 2 (BCL2). Dual blockade with ERBB2 and BCL2 inhibitors triggers additional reductions of BCL2 phosphorylation and myeloid cell leukemia protein 1 (MCL1) expression compared to single drug treatment. Dual therapy was synergistic at all tested doses, with a dose reduction index of up to 29 for lapatinib + venetoclax compared to venetoclax alone. Notably, these agents operated together and shifted cancer cells to a pro-apoptotic phenotype, resulting in increased mitochondrial cytochrome c release and activated caspase-3-mediated cell death. Implications: These findings warrant study of ERBB2 and BCL2 combination therapy in patients with MDS and AML.

Full Text

Duke Authors

Cited Authors

  • Kam, AYF; Piryani, SO; Lee, C-L; Rizzieri, DA; Spector, NL; Sarantopoulos, S; Doan, PL

Published Date

  • January 29, 2021

Published In

PubMed ID

  • 33514658

Pubmed Central ID

  • 33514658

Electronic International Standard Serial Number (EISSN)

  • 1557-3125

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.MCR-20-0973

Language

  • eng

Conference Location

  • United States