Selitrectinib is the Second-Generation TRK Inhibitor for Non-Small Cell Lung Cancer Research

Belonging to a tyrosine kinase family, TRK receptors (TRKA/B/C)—are significantly involved in embryonic neuronal development and differentiation. Moreover, TRKA/B/C play specialized roles in controlling vital functions like pain, movement, mood, memory, appetite, body weight, proprioception, and thermoregulation. However, the scenario takes a sinister turn when these proteins mutate. They can then act as a catalyst for cancer growth, leading to dreadful diseases such as Non-Small Cell Lung Cancer (NSCLC). NSCLC claims 85% of all lung cancer cases, showing diverse behaviors and response rates across its multiple subtypes.

Enter Selitrectinib (LOXO-195), a second-generation inhibitor that dominates this stage by overcoming resistance mutations. It binds with the ATP pocket of the target kinase with increased precision and affinity, targeting both wild-type and mutant kinases effectively. The tireless pursuit for adequate therapy options continues against NSCLC. Amidst this struggle, Selitrectinib emerges as a beacon of hope.

Selitrectinib is a TRK inhibitor for non-small cell lung cancer research.

In vitro, Selitrectinib, shows a potent affinity towards wild-type TRKA/B/C, with an IC₅₀ less than 1 nM. Intriguingly, Selitrectinib is also active against mutations such as TRKA G595R, TRKC G623R, and TRKA G667C, with IC₅₀s from 2.0 to 9.8 nM. Remarkably, Selitrectinib is more than 1000-fold selective for 98% of the non-TRK kinases tested. Moreover, it robustly inhibits cell proliferation in TRK fusion-containing cell lines, including KM12, CUTO-3, and MO-91 (IC₅₀ ≤ 5 nM).

In vivo, stably transfected NIH-3T3 ΔTRKA and ΔTRKA-G595R cells are implanted subcutaneously into the flanks of nude mice. In this scenario, both Larotrectinib and Selitrectinib effectively reduces phosphorylated TRKA in tumors driven by ΔTRKA. Furthermore, Selitrectinib inhibits tumor growth in four TRKA-dependent tumor models, namely ΔTRKA, ΔTRKA-G595R, ΔTRKAG667C, and TPM3-NTRK1 fusion-positive KM12 colorectal cancer cells.

In summary, Selitrectinib is an effective wild-type and mutant TRK kinase inhibitor, and can be used for non-small cell lung cancer research.

References:

[1] Harada G, et al. TRK Inhibitors in Non-Small Cell Lung Cancer. Curr Treat Options Oncol. 2020 Apr 23;21(5):39.

[2] Drilon A, et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov. 2017 Sep;7(9):963-972.