Brian K Law, Ph.D.

Some of the Law Lab’s primary research interests revolves around cyclin-dependent kinases (Cdks) in mammary tumorigenesis and chromosomal instability, and Cdk regulation by the mTOR and TGFβ pathways. This research involves the use of novel models to understand how the activation of Cdks in the mammary gland causes tumor formation by dysregulation of cell proliferation and through genetic alterations that result from chromosomal instability. These models also provide systems for testing new therapeutic strategies, including non-ATP competitive Cdk inhibitors discovered in their laboratory and for targeting the upstream signaling pathways, such as the mTOR and TGFβ axes, that stimulate Cdk kinase activity.

Other Areas of Interest

Mechanisms by which CDCP1 Promotes Breast Cancer Metastasis: The CDCP1 protein functions as a scaffold to bring together and facilitate synergy between the oncoproteins Epidermal Growth Factor Receptor (EGFR) and the Src tyrosine kinase. This results in disassembly of cell-cell and cell-substratum adhesion complexes and may facilitate cancer metastasis by permitting cancer cell invasion and de-adhesion. Current work is directed toward identifying pharmacological strategies to block the pro-metastatic functions of CDCP1. (Law, M., et al. Oncogene (2013) 32:1316; Law, M., et al. Breast Cancer Research (2016) 18:80)

Activation of Death Receptors 4 and 5 by Altered Disulfide Bonding as a New Approach to Cancer Therapy: Our collaborative team identified a novel class of anticancer agents termed Disulfide bond Disrupting Agents (DDAs). DDAs selectively kill cancer cells that overproduce the oncoproteins Epidermal Growth Factor Receptor (EGFR/HER1), the EGFR family member, HER2, or the transcription factor MYC. DDA-induced cell death is mediated by the Death Receptors DR4 and DR5, which activate the Caspase 8-Caspase 3 pro-apoptotic cascade. Current work focuses on elucidating the molecular mechanisms by which DDAs activate DR4/5. (Wang, M., et al. Cell Death Discovery (2019) 5:153; Wang, M., et al., Oncogene (2019) 38:4264)   Identification of the First Active Site Inhibitors of the Disulfide Isomerases ERp44 and AGR2 as Novel Anticancer Agents: Affinity-tagged DDA molecules were used to identify the Protein Disulfide Isomerases ERp44, AGR2/3, and PDIA1 as the direct DDA target proteins in cancer cells that mediate DDA actions. Ongoing efforts are focused on understanding the structural features of the DDAs and their target proteins that control DDA target selectivity, and on determining the role of the DDA target enzymes in regulating the disulfide bonding patterns of their client proteins, Death Receptors 4 and 5, and the HER-family receptor tyrosine kinases EGFR and HER2. (Law, M., et al. bioRxiv preprint doi: https://doi.org/10.1101/2021.01.13.426390)

• Cancer
• Cell Cycle Regulation
• Drug discovery