Ibrutinib as a potential therapeutic option for HER2+ breast cancer – the role of STAT3 and p21
Date
2019-12-16
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
Abstract
Treatment options for HER2 overexpressing breast cancer are limited, and the current anticancer therapies are associated with side effects. Tyrosine kinases perform crucial roles in cell proliferation, differentiation, and signal transduction process. Hence, tyrosine kinase inhibitors (TKIs) have been investigated as potential therapeutic options in the treatment of cancers. Ibrutinib (Imbruvica), an FDA approved tyrosine kinase inhibitor (TKI) for BTK, has shown to be effective in HER2 overexpressing breast cancer cell lines. However, the exact mechanism of action of ibrutinib in HER2 overexpressing breast cancer remains unknown. In this study, we have performed a kinome array analysis of ibrutinib treatment in two HER2 overexpressing breast cancer cell lines - BT474 and SKBR3. Our analysis shows that ibrutinib induces apoptosis through the activation of caspase-8, caspase-3, and PARP1 via the caspase-dependent extrinsic pathway. This result was further supported by changes in nuclear morphology, pSTAT3Y705 upregulation and p21T145 downregulation in both of the cell lines on treatment with ibrutinib. We for the first time show the involvement of the STAT3-p21 axis in bringing about apoptosis and propose that STAT3 activation is a passive response against DNA damage to promote cell cycle progression. These results have application in understanding the possible mechanism of action of ibrutinib in these cell lines and also suggest that inhibitors of pSTAT3 may be potential options for combination therapy with ibruitnib in HER2-overexpressing tumors.
Description
Keywords
HER2, Ibrutinib, STAT3 and p21
Citation
Degree
Master of Science (M.Sc.)
Department
Pharmacy and Nutrition
Program
Pharmacy