Selpercatinib

Brand Name: Retevmo

Selpercatinib is used to treat non-small cell lung cancer, thyroid cancer, and locally advanced or metastatic solid tumors with a RET gene fusion.1

How Does Selpercatinib Work?

Tyrosine kinase uses ATP to attach a phosphate tag on other proteins in a process called phosphorylation. This 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

RET protein on the surface of the cell.

RET 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

Monomeric RET tyrosine kinase is inactive. Dimeric RET tyrosine kinase is active.

The kinase domain of RET is inactive by itself, but when two kinase domains come together to form a dimer, the kinase is activated. Active RET kinases then phosphorylate itself and other proteins to transmit growth signals.3

Two RET proteins are separated on the surface of the cell.

In normal conditions, RET does not associate with each other and remains monomeric and inactive.3

Receptor binding to GFR and GFL results in RET dimerization.

On the other hand, in the presence of a growth factor called GFL4, as well as a co-receptor called GFR5, the receptor domain of RET dimerizes.

Active RET transmits growth signal through phosphorylation.

This brings two kinase domains of ALK together and activates them to transmit growth signals through phosphorylation.6 Of note, because the dimerization of ALK requires the binding of growth factors, growth signaling transmitted by ALK is controllable; when cell growth is no longer necessary, growth factor production ceases, which returns ALK to its inactive monomeric form.3

Mutated RET with its receptor domain replaced with a coiled-coil domain.

In some types of cancer, a mutation in the ALK gene results in the replacement of the receptor domain of ALK with part of another protein like KIF5B or CCDC6. This commonly results in a fusion RET protein that has a RET kinase domain connected to a type of protein structure called a coiled-coil (CC) domain.7

Two RET fusion proteins bind together to form an active dimer.

Coiled-coil domains are intrinsically able to dimerize, so the kinases of RET fusion proteins are constitutively active.7

Growth signal level ranges from no signal from inactive RET, to controlled signal from active RET dimer, to cancerous signal from RET fusion protein.

This leads to an uncontrolled phosphorylation by RET fusion proteins, and the resulting surge in growth signals leads to cancer proliferation.3

Selpercatinib blocks the ATP-binding site of RET fusion protein and stops growth signal transmission.

Selpercatinib is a type of drug called kinase inhibitors. It blocks the kinase domain of RET fusion protein from accessing the ATP required for phosphorylation.8 This turns off the growth signal, and as a result, cancer growth is halted.

References

1. RETEVMO - Label. U.S. Food and Drug Administration (2022).

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

3. Mulligan, L. M. RET revisited: expanding the oncogenic portfolio. Nature Reviews Cancer 14, 173-186 (2014).

4. Trupp, M. et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381, 785-789 (1996).

5. Jing, S. et al. GDNF-Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF. Cell 85, 1113-1124 (1996).

6. Besset, V., Scott, R. P. & Ibáñez, C. F. Signaling Complexes and Protein-Protein Interactions Involved in the Activation of the Ras and Phosphatidylinositol 3-Kinase Pathways by the c-Ret Receptor Tyrosine Kinase. Journal of Biological Chemistry 275, 39159-39166 (2000).

7. Takeuchi, K. et al. RET, ROS1 and ALK fusions in lung cancer. Nature Medicine 18, 378-381 (2012).

8. Subbiah, V. et al. Selective RET kinase inhibition for patients with RET-altered cancers. Annals of Oncology 29, 1869-1876 (2018).