Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications.

Abstract

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. Mol Cancer Ther; 15(4); 628-39. ©2016 AACR.

• Authors: Elena Ardini, Maria Menichincheri, Patrizia Banfi, Roberta Bosotti, Cristina De Ponti, Romana Pulci, Dario Ballinari, Marina Ciomei, Gemma Texido, Anna Degrassi, Nilla Avanzi, Nadia Amboldi, Maria Beatrice Saccardo, Daniele Casero, Paolo Orsini, Tiziano Bandiera, Luca Mologni, David Anderson, Ge Wei, Jason Harris, Jean-Michel Vernier, Gang Li, Eduard Felder, Daniele Donati, Antonella Isacchi, Enrico Pesenti, Paola Magnaghi, Arturo Galvani
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 4 Pg. 628-39 (04 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 26939704 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Benzamides
• Indazoles
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• ALK protein, human
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• ROS1 protein, human
• Receptor Protein-Tyrosine Kinases
• entrectinib

Topics

• Anaplastic Lymphoma Kinase
• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides (chemistry, pharmacology)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Humans
• Indazoles (chemistry, pharmacology)
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Transgenic
• Mortality
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Translocation, Genetic
• Treatment Outcome
• Xenograft Model Antitumor Assays