The Challenge and Opportunity of NTRK Inhibitors in Non-Small Cell Lung Cancer

Abstract

With the development of targeted therapy, non-small cell lung cancer (NSCLC) patients could have more treatment choices if target mutation presents. The neurotrophic tropomyosin receptor kinase (NTRK) has a low prevalence in NSCLC, roughly around 0.5%. FDA had approved two first generation NTRK inhibitors, larotrectinib and entrectinib. Both medications have excellent CNS penetration. This manuscript will review available data on targeting NTRK fusions in NSCLC and mechanisms of drug resistance.

Keywords: NTRK; drug resistance; non-small cell lung cancer.

Figure 1

NTRK downstream signal pathway and function. NTRK has the typical structure of extracellular ligand binding domains, a transmembrane region, and intracellular kinase domain. When NTRK binds with its ligand, the downstream PI3K/MAPK/PLC pathway will be activated and cause cell survival, proliferation, and differentiation. BDNF—brain-derived neurotrophic factor; NT4—neurotrophin 4; NGF—neurotrophin nerve growth factor; NT3—neurotrophin 3; PI3K—Phosphoinositide 3-kinase; MAPK—Mitogen-activated protein kinase; PLC—Phospholipase C.

Figure 2

Timeline of NTRK genes and NTRK inhibitor therapy.

Figure 3

Oncogenesis pathway of NTRK fusion protein. The tyrosine kinase domain of NTRK fuses with the 5′ region of a partner gene, producing a chimeric protein. This fusion protein leads to constitutive activation of downstream pathways, resulting in ligand independent pathway signaling and subsequently cause oncogenesis. NTRK inhibitors are able to treat NTRK fusion malignancy by blocking the tyrosine kinase, hampering the signal pathway in both wide type and fusion protein producing tumor cells.

Figure 4

Drug-resistance mechanism of NTRK inhibitors and treatment algorithm. In NTRK fusion solid tumors, 1st generation NTRK inhibitors can achieve reasonable disease control. If there is only solitary site progression or oligoprogression, then 1st generation NTRK inhibitors can be continued while adding local therapy such as radiation or surgery. If drug resistance occurs to the 1st generation NTRK inhibitors, either through on-target or off-target mechanisms, a second generation NTRK inhibitor can be used to control the disease. If there are multiple targeted mutations, then combined therapy should be attempted to control the disease progression [43]. When the patient has no further targeted therapy after either 1st or 2nd generation NTRK inhibitors, then standard chemotherapy or clinical trials should be offered.