Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers

Abstract

() gene rearrangement leads to constitutive activation of NTRK1, which induces high-transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non-small cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKI), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecule inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or larotrectinib (LOXO-101). Furthermore, cabozantinib with an IGF1R inhibitor such as OSI-906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. .

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…The true oncogenic potential of non-fusion NTRK alterations, such as mutations, gene amplifications and alternative splicing has yet to be confirmed [49,50,[82][83][84][85][86]. Moreover, as it will be furtherly discussed later, these alternative types of alterations can play a crucial role in tumor resistance against NTRK-fusions inhibitors and therefore are being increasingly investigated [70,87].…”

Revisiting NTRKs as an emerging oncogene in hematological malignancies

“…Apart from the aforementioned inhibitors, many others have been validated in solid tumors bearing NTRK fusions or mutations. These include cabozantinib [109], foretinib [109], merestinib [110], and nintedanib [109] among others. Moreover, IGF1R/IR pathway inhibitors, in particular, have shown to be effective at blocking EN activity by initiating a process that results in the ubiquitylation and proteasomal degradation of the fusion protein itself [96].…”

Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer

“…Molecular modeling studies suggest that MET F1200I alters the conformation of the kinase domain such that it interferes with both the binding of type II MET TKIs within the DFG-out binding pocket, and to a lesser extent, may promote type I MET TKI resistance through disruption of an autoinhibitory MET conformation (Supplemental Figure S2) (7). Moreover, the F1200 residue is conserved across multiple tyrosine kinases, including ALK, ROS1, NTRK, and ABL, in which mutations at the corresponding residue have been linked to TKI resistance (Supplemental Table 4) (21)(22)(23)(24)(25)(26)(27).…”