Targeting ABL-Dependent Brain Metastatic Targets in HER2-Positive Breast Cancer

By: Victoria Kuhr, BA
Posted: Wednesday, January 4, 2023

Ann Marie Pendergast, PhD, of Duke University, Durham, North Carolina, and colleagues proposed that ABL kinase allosteric inhibitors may improve outcomes and impair HER2-positive brain metastatic outgrowth in vivo in preclinical studies. Additionally, the researchers suggested that ABL kinase inhibition may decreases the translation of HER2 and disrupt YB-1 (Y-box–binding protein) binding to the ERBB2 mRNA coding sequence in brain metastatic cells from breast cancer. These study findings were published in Cell Reports.

“These findings support the use of ABL kinase inhibitors for the treatment of HER2-positive brain metastasis,” said Dr. Pendergast in a Duke Health press release.

The study investigators treated mice bearing intracranial tumors with vehicle or the ABL kinase allosteric inhibitor GNF5. Treatment with GNF5 decreased colonization of the brain parenchyma and increased overall survival in mice compared with the vehicle, according to the study findings.

When the brain tumor HCC1954-LCC1 cell lysates were analyzed, ABL kinase activity was shown to decrease 80% in the GNF5-treated mice. The authors believe this was attributable to decreased phosphorylation of the ABL substrate CrkL. The viability of tumor cells was reduced by CRISPR knockout of ABL1 and ABL2. These findings suggest that CRISPR knockout of ABL1 and ABL2 in HCC1954-LCC1 cells may decrease brain tumor burden and improve outcomes after intracranial injection. Pharmacologic and genetic inhibition of ABL kinases resulted in little to no change in ERBB2 mRNA levels, the study authors found. This finding suggests that transcriptional regulation of ERBB2 is unlikely to be the principal contributor to the decrease in HER2 protein expression.

Additionally, YB-1 localizes to the cytosol, and knockdown of YB-1 did not seem to affect ERRB2 mRNA levels. The loss of YB-1 impaired metastatic outgrowth in the brain by targeting the ERBB2 mRNA. These results suggest that YB-1 may promote HER2 translation in breast cancer brain metastases without altering ERBB2 transcription.

Disclosures: For full disclosures of the study authors, visit www.cell.com.

Cell Reports

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