Dr González-González on DDR Pathway Inhibition in HER2-low TNBC Breast Cancer Models

Adrian González-González, postdoctoral research associate, Washington University School of Medicine in St. Louis, discusses findings from a preclinical study of fam-trastuzumab deruxtecan-nxki (Enhertu) in combination with DNA damage response (DDR) pathway inhibitors in xenograft models derived from patients with HER2-low triple-negative breast cancer (TNBC).

This study investigated whether the DNA damaging effect of trastuzumab deruxtecan could be increased with the addition of small molecule inhibitors of DDR pathways to improve antitumor activity in HER2-low TNBC. In the in vivo portion of this study, mice injected with HER2-low TNBC tumor cells from patient-derived xenograft models were randomized to receive trastuzumab deruxtecan and/or DDR pathway inhibitors, including the ATM inhibitor AZD1390, the ATR inhibitor AZD6738, the PARP inhibitor olaparib (Lynparza), the AKT inhibitor AZD5363, and the WEE 1 inhibitor AZD1775. Over 3 weeks of treatment, the investigators analyzed tumor volume changes compared with baseline volumes. At the end of the 3-week period, samples from the surviving mice were analyzed for DNA damage and apoptosis biomarker expression. The investigators also performed an in vitro mechanistic analysis of these agents in HER2-low TNBC cell lines.

Findings from the in vivo portion of this study showed that trastuzumab deruxtecan plus olaparib reduced tumor volume and promoted survival in the mice that received the combination, González-González says. Additionally, the in vitro analysis showed that the aggressive behavior of the cancer cells was reduced when treated with trastuzumab deruxtecan plus olaparib, González-González explains.

A migration assay revealed that trastuzumab deruxtecan plus olaparib significantly reduced the migration index in HCC1806, BT549, and WHIM 12 cells. A migration reduction also occurred with the combination of trastuzumab deruxtecan and an ATR inhibitor in HCC1806 and WHIM 12 cells. Furthermore, a biomarker evaluation of epithelial-mesenchymal transition transcription factors showed that treatment with trastuzumab deruxtecan and olaparib was associated with lower epithelial-mesenchymal transition transcription factor expression in most cell lines evaluated. Overall, the combination of olaparib and trastuzumab deruxtecan has promising efficacy in HER2-low TNBC stem cells, González-González concludes.