entrectinib and Brain-Neoplasms

Entrectinib, a ROS-1 inhibitor, has been shown to be effective for patients with ROS-1 fused NSCLC, and has been established as the standard of care for this population. Entrectinib has been shown to achieve a better response to brain metastasis due to the characteristic of the drug having a weak interaction with P-glycoprotein and, even in prospective studies, the intracranial response is higher. Patients have been known to acquire resistance to molecularly targeted drugs such as EGF-TKIs or ALK-TKIs during targeted therapy. Similarly, the mechanisms of resistance to entrectinib have been reported, but information about the effects of TP53 mutation with entrectinib are still limited. Here, we experienced a case of a patient with ROS-1 fusion and concurrent TP53 mutation who was treated with entrectinib, resulting in a response to brain metastasis but rapid resistance to entrectinib. Our case demonstrates both the intracranial activity of entrectinib and the potential for resistance to entrectinib due to TP53 mutation.

Topics: Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Prospective Studies; Protein Kinase Inhibitors; Reactive Oxygen Species; Tumor Suppressor Protein p53

Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

Topics: Benzamides; Brain Neoplasms; ErbB Receptors; Humans; Indazoles; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Receptor, trkA

Topics: Benzamides; Brain Neoplasms; Clinical Trials as Topic; Gene Fusion; Humans; Indazoles; Pyrazoles; Pyrimidines

Topics: Amino Acid Substitution; Anilides; Animals; Benzamides; Brain Neoplasms; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Heterografts; Humans; Indazoles; Mice; Models, Molecular; Mutation; Oncogene Proteins, Fusion; Quinolines; Receptor, trkA; Structure-Activity Relationship

To accurately recapitulate the heterogeneity of human diseases, animal models require to recreate multiple complex genetic alterations. Here, we combine the RCAS-TVA system with the CRISPR-Cas9 genome editing tools for precise modeling of human tumors. We show that somatic deletion in neural stem cells of a variety of known tumor suppressor genes (Trp53, Cdkn2a, and Pten) leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs we generate different gene fusions with oncogenic potential, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk). Lastly, using homology-directed-repair, we also produce tumors carrying the homologous mutation to human BRAF V600E, frequently identified in a variety of tumors, including different types of gliomas. In summary, we have developed an extremely versatile mouse model for in vivo somatic genome editing, that will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing.

Topics: Animals; Antigens, Neoplasm; Benzamides; Brain Neoplasms; Brevican; CRISPR-Cas Systems; DNA Repair; False Positive Reactions; Gene Editing; Gene Frequency; Gene Transfer Techniques; Glioma; Humans; In Situ Hybridization, Fluorescence; Indazoles; Mice; Mice, SCID; Mice, Transgenic; Mutation; NIH 3T3 Cells; Receptor, trkA; RNA, Guide, Kinetoplastida