title: 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.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy. elena.ardini@nervianoms.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Ardini
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banfi
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bosotti
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: De Ponti
authors.affiliation: Accelera srl, Nerviano, Milan, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Pulci
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Texido
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Degrassi
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Amboldi
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Saccardo
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Casero
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsini
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: David
authors.initials: D
authors.lastname: Anderson
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Ge
authors.initials: G
authors.lastname: Wei
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Harris
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vernier
authors.affiliation: Ignyta, Inc., San Diego, California.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Eduard
authors.initials: E
authors.lastname: Felder
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: Accelera srl, Nerviano, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Magnaghi
authors.affiliation: Nerviano Medical Sciences srl, Nerviano, Milan, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009026:Mortality; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014178:Translocation, Genetic; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C000607349:entrectinib