Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

Abstract

Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics.Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by nextgeneration sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors.Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1. The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro. Moreover, foretinib markedly inhibited the progression of entrectinib-refractory KM12SM-ER-derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation.Conclusions: These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the NTRK1-G667C mutation in NTRK1 fusion-positive tumors in various organs, including the brain, and provide a rationale for clinical trials of foretinib in cancer patients with entrectinibresistant tumors harboring the NTRK1-G667C mutation, including patients with brain metastases. Clin Cancer Res; 1-13. Ó2018AACR.

Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials

“…15 Consistent with these findings, entrectinib was found to prolong survival and delay intracranial progression compared to vehicle in orthotopic CNS xenografts of models that harbour established fusion targets of the drug such as NCI-H228 (NSCLC), 13 BNN2/4 (glioblastoma), 16 and KM12SM (colorectal cancer). 17 In the NCI-H228 model, entrectinib resulted in increased survival compared to crizotinib. These data established preclinical proof-of-principle of the activity of this drug in the CNS.…”

Synthesis, biological evaluation, and molecular modeling of 11H-indeno[1,2-b]quinoxalin-11-one derivatives and tryptanthrin-6-oxime as c-Jun N-terminal kinase inhibitors

“…Note however, that IQ-1 and IQ-3 (both potent JNK inhibitors with an indenoquinoxaline scaffold) did not bind TRK-A [29, 30]. Because TRKA-C are important targets for treatment of several tumors [40–42], the parent tryptanthrin and tryptanthrin-6-oxime were evaluated for their binding affinities (K d ) to these 3 kinases. We found that tryptanthrin-6-oxime had higher affinity toward TRKA-C in comparison with the parent alkaloid (Table 2).…”

Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer

“…Moreover, in a brain metastasis model with NTRK1-fusion-positive colon cancer cells, the NTRK1-G667C mutation (which caused moderate resistance), but not the NTRK1-G595R mutation (which induced high resistance), was detected in tumor cells resistant to the TRK inhibitor entrectinib. 35 Therefore, high-dose administration of drugs, which target a driver signal (for instance, an alectinib versus ALK signal) or combined use of standard-dose alectinib and another drug that targets resistance signals (e.g., EGFR TKIs to inhibit an AREG-triggered EGFR signal) may be useful to control resistance in CNS.…”