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Supplementary Tables, Figures, References from Selective ERBB2 and BCL2 Inhibition Is Synergistic for Mitochondrial-Mediated Apoptosis in MDS and AML Cells

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posted on 2023-04-03, 19:46 authored by Angel Y.F. Kam, Sadhna O. Piryani, Chang-Lung Lee, David A. Rizzieri, Neil L. Spector, Stefanie Sarantopoulos, Phuong L. Doan

Supplemental Table 1. AML Patient demographics Supplemental Table 2. MDS Patient demographics Figure S1. ERBB2 is overexpressed and truncated in MDS and AML cells. Figure S2. Lapatinib effectively reduces levels of phospho-ERBB2 in MDS-L and K562 cells. Figure S3. ERBB2 inhibition with Lapatinib impairs MDS and AML cell proliferation. Figure S4. Afatinib and neratinib promotes leukemic cell death. Figure S5. ERBB2 inhibition with Lapatinib decreases MDS xenograft. Figure S6. Inhibition of MCL1 by AZD5991 enhances MDS-L cell death. Figure S7. Dual inhibition of ERBB2 and BCL-2 is synergistic to promote cancer death compared to monotherapy.

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ARTICLE ABSTRACT

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 with 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 posttransplantation. 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-1 (MCL1) expression compared with single drug treatment. Dual therapy was synergistic at all tested doses, with a dose reduction index of up to 29 for lapatinib + venetoclax compared with 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. These findings warrant study of ERBB2 and BCL2 combination therapy in patients with MDS and AML.

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