Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines

by Selleckchem | Aug 26 2023

Small molecule Bruton's tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitor for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer (BCa). This subtype of breast cancer belongs to one of the most common classes of breast tumours, and its prognosis is characterized by a high rate of recurrence and tumour invasiveness. Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway. We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive BCa cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.

Comments:

The development of small molecule Bruton's tyrosine kinase (BTK) inhibitors has shown promise in the treatment of various haemato-oncological diseases. Ibrutinib, the first BTK inhibitor approved for anticancer therapy in 2013, has been found to target the receptor kinase human epidermal growth factor receptor 2 (HER2) as an off-target kinase. This observation, along with the fact that HER2-positive breast cancer (BCa) is a common and aggressive subtype of breast cancer, led researchers to investigate the potential of repurposing ibrutinib and other irreversible BTK inhibitors for the treatment of HER2-positive BCa.

In the study you mentioned, the researchers evaluated the anticancer effects of four BTK inhibitors - zanubrutinib, evobrutinib, tirabrutinib, and acalabrutinib - in different BCa cell lines. They specifically focused on determining whether these inhibitors targeted the epidermal growth factor receptor family (ERBB) pathway, which is closely related to HER2 signaling.

The findings indicated that zanubrutinib, one of the BTK inhibitors, showed potential as an inhibitor of the HER2 signaling pathway. Zanubrutinib exhibited an antiproliferative effect in HER2-positive BCa cell lines and effectively inhibited the phosphorylation of proteins involved in the ERBB signaling cascade. This included downstream kinases such as Akt and ERK, which play crucial roles in promoting cancer cell survival and proliferation.

Based on these results, the researchers proposed zanubrutinib as a suitable candidate for repurposing in HER2-amplified solid tumors, including HER2-positive BCa. Repurposing existing drugs like zanubrutinib for new indications can provide a faster and potentially more cost-effective approach to drug development, as these drugs have already undergone extensive safety testing and optimization.

It's important to note that while the study suggests zanubrutinib's potential as a HER2 inhibitor, further research, including preclinical and clinical studies, is needed to fully understand its efficacy and safety in the treatment of HER2-positive BCa.