Fam-Trastuzumab Deruxtecan-nxki

Brand Name: Enhertu

Fam-trastuzumab deruxtecan-nxki is used to treat HER2-positive or HER2-low unresectable or metastatic breast cancer, locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma, unresectable or metastatic non-small cell lung cancer (NSCLC) with HER2-activating mutation, and unresectable or metastatic HER2-positive solid tumors.1

How Does Fam-Trastuzumab Deruxtecan-nxki Work?

Tyrosine kinase using ATP to attach a phosphate tag on other proteins, which results in the transmission of growth signals.

Cellular growth signals are often transmitted through a process called phosphorylation, in which an enzyme called tyrosine kinase attaches a phosphate tag to another protein. This phosphate tag is derived from a molecule called ATP.2

HER2 protein on the surface of the cell.

HER2 is a protein in the receptor tyrosine kinase family. This protein consists of a receptor domain outside the cell connected to a tyrosine kinase domain inside the cell.3

Inactive monomeric HER2 tyrosine kinase domain and active dimeric HER2 tyrosine kinase domains.

The kinase domain of HER2 is inactive by itself, but when two kinase domains come together to form a dimer, the kinase is activated, allowing phosphorylation to transmit growth signals.3

HER2 and EGFR or HER3 dimer producing controlled growth signals.

HER2 is activated during specific stages of development by dimerizing with other similar proteins, such as EGFR or HER3. It is responsible for the development of various organs, such as the heart and the mammary gland.4,5 Of note, the expression level of HER2 is tightly controlled so that growth signals are generated only when necessary.

HER2 and EGFR or HER3 dimer as well as HER2 and HER2 dimer producing uncontrolled growth signals.

However, in some types of cancer, HER2 is overexpressed. Due to enhanced pairing of HER2 with other similar proteins and also itself, uncontrolled growth signals are produced that drive cancer proliferation.3

Fam-trastuzumab deruxtecan-nxki binding to receptor domain of HER2.

Fam-trastuzumab deruxtecan-nxki is an antibody-drug conjugate that comprises of toxic molcules called DXd attached to an antibody called trastuzumab, which can specifically recognize and bind to HER2.6

Fam-trastuzumab deruxtecan-nxki entering the cell and releasing DXd

(1) When fam-trastuzumab deruxtecan-nxki binds to HER2, it can get internalized into the cell along with HER2. (2) Some internalized HER2 proteins are degraded, which releases DXd that can kill the cell. Since trastuzumab specifically recognizes HER2, cells expressing the highest amounts of HER2, i.e. the cancer cells, are targeted for killing, while most other cells are spared.6

References

1. ENHERTU - Label. U.S. Food and Drug Administration (2024).

2. Hubbard, S. R. & Till, J. H. Protein Tyrosine Kinase Structure and Function. Annual Review of Biochemistry 69, 373-398 (2000).

3. Tebbutt, N., Pedersen, M. W. & Johns, T. G. Targeting the ERBB family in cancer: couples therapy. Nature Reviews Cancer 13, 663-673 (2013).

4. Lee, KF. et al. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378, 394-398 (1995).

5. Stern, D. F. ErbBs in mammary development. Experimental Cell Research 284, 89-98 (2003).

6. Ogitani, Y. et al. DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1. Clinical Cancer Research 22, 5097-5108 (2016).