title: The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice.
abstract: Activation of anaplastic lymphoma receptor tyrosine kinase (ALK) is involved in the pathogenesis of several carcinomas, including non-small cell lung cancer (NSCLC). Echinoderm microtubule-associated protein like 4 (EML4)-ALK, which is derived from the rearrangement of ALK and EML4 genes, has been validated as a therapeutic target in a subset of patients with NSCLC. Here, we investigated the effects of ASP3026, a novel small-molecule ALK inhibitor, against ALK-driven NSCLC. ASP3026 inhibited ALK activity in an ATP-competitive manner and had an inhibitory spectrum that differed from that of crizotinib, a dual ALK/MET inhibitor. In mice xenografted with NCI-H2228 cells expressing EML4-ALK, orally administered ASP3026 was well absorbed in tumor tissues, reaching concentrations >10-fold higher than those in plasma, and induced tumor regression with a wide therapeutic margin between efficacious and toxic doses. In the same mouse model, ASP3026 enhanced the antitumor activities of paclitaxel and pemetrexed without affecting body weight. ASP3026 also showed potent antitumor activities, including tumor shrinkage to a nondetectable level, in hEML4-ALK transgenic mice and prolonged survival in mice with intrapleural NCI-H2228 xenografts. In an intrahepatic xenograft model using NCI-H2228 cells, ASP3026 induced continuous tumor regression, whereas mice treated with crizotinib showed tumor relapse after an initial response. Finally, ASP3026 exhibited potent antitumor activity against cells expressing EML4-ALK with a mutation in the gatekeeper position (L1196M) that confers crizotinib resistance. Taken together, these findings indicate that ASP3026 has potential efficacy for NSCLC and is expected to improve the therapeutic outcomes of patients with cancer with ALK abnormality.
authors.affiliation: Corresponding Author: Masamichi Mori, Pharmacology Research Labs, Oncology, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. masamichi.mori@astellas.com.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mori
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ueno
authors.forename: Satoshi
authors.initials: S
authors.lastname: Konagai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fushiki
authors.forename: Itsuro
authors.initials: I
authors.lastname: Shimada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Rika
authors.initials: R
authors.lastname: Saito
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mori
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shindou
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Hideki
authors.initials: H
authors.lastname: Sakagami
authors.forename: Takashi
authors.initials: T
authors.lastname: Furutani
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Doihara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kudoh
authors.forename: Sadao
authors.initials: S
authors.lastname: Kuromitsu
mesh_terms: D016475:3T3 Cells; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology; D000068437:Pemetrexed; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016019:Survival Analysis; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595153:ASP3026; D000970:Antineoplastic Agents; D005971:Glutamates; D047428:Protein Kinase Inhibitors; D013450:Sulfones; D014227:Triazines; D000068437:Pemetrexed; D006147:Guanine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D017239:Paclitaxel