Abstract 2092: The ALK inhibitor NMS-E628 also potently inhibits ROS1 and induces tumor regression in ROS-driven models .
Authors: Ardini Elena , Menichincheri Maria , Banfi Patrizia , Casero Daniele , Giorgini M.Laura , Saccardo M. Beatrice , Amboldi Nadia , Avanzi Nilla , Orsini Paolo , Isacchi Antonella , Pesenti Enrico , Galvani Arturo 
Published: August 2014

ROS1 is a receptor tyrosine kinase belonging to the Insulin Receptor family. It was originally identified in glioblastoma where it is involved in a chromosomal rearrangement that generates an oncogenic FIG-ROS1 fusion gene. More recently, through the application of advanced genomic approaches a series of new chromosomal rearrangements involving ROS1 gene have been identified in Non-Small Cell Lung Cancer (NSCLC) tumors. The fusion genes that have been characterized to date, such as for example SCL34A2-ROS1, result in expression of chimeric proteins endowed with constitutive tyrosine kinase activity. As already observed for ALK, the ROS positive patient population (ca 1% of NSCLC) is characterized by specific features: all tumors are adenocarcinoma and patients tend to be non-smokers and younger that the median age of NSCLC patients.

NMS-E628 is an orally available small-molecule inhibitor of ALK kinase activity that is currently being evaluated in phase I/II clinical study. In preclinical models, NMS-E628 potently and selectively inhibits the in vitro and in vivo growth of ALK-driven tumors, with confirmed mechanism of action. Since NMS-E628 is able to pass the blood-brain barrier, the compound was also tested for efficacy in an intracranial xenograft model with ALK positive NSCLC tumors. MRI imaging demonstrated that NMS-E628 was able to effectively and dose-dependently control the growth of these intracranial tumors, leading to increased survival.

Due to the structural similarity between ALK and ROS1 kinases, the activity of NMS-E628 on ROS1 was evaluated in biochemical and cellular assays. The compound was found to be a potent, ATP competitive inhibitor of ROS1 (IC50 7 nM). This biochemical potency translates into inhibition of the proliferation of HCC-78, a NSCLC cell line characterized by ROS1-driven activated signaling, due to the presence of the SCL34A2-ROS1 fusion gene. To further characterize the compound in cells, an activated form of ROS1 was expressed in Ba/F3 cells generating an IL3-independent, ROS1-driven tumor model. NMS-E628 strongly inhibits the proliferation of Ba/F3-ROS1 cells in vitro with confirmed dose-dependent decrease of ROS1 phosphorylation. When tested in vivo, the compound was found to induce complete tumor regression after 10-day continuous treatment in nude mice bearing established Ba/F3-ROS1 tumors.

Taken together, these data indicate that NMS-E628 might represent a valid therapeutic opportunity for patients bearing ROS1-dependent tumors.

Citation Format: Elena Ardini, Maria Menichincheri, Patrizia Banfi, Daniele Casero, M.Laura Giorgini, M. Beatrice Saccardo, Nadia Amboldi, Nilla Avanzi, Paolo Orsini, Antonella Isacchi, Enrico Pesenti, Arturo Galvani. The ALK inhibitor NMS-E628 also potently inhibits ROS1 and induces tumor regression in ROS-driven models . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2092. doi:10.1158/1538-7445.AM2013-2092