The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.

Abstract

ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.

• Authors: Ryohei Katayama, Bo Gong, Noriko Togashi, Masaya Miyamoto, Masaki Kiga, Shiho Iwasaki, Yasuki Kamai, Yuichi Tominaga, Yasuyuki Takeda, Yoshiko Kagoshima, Yuki Shimizu, Yosuke Seto, Tomoko Oh-Hara, Sumie Koike, Naoki Nakao, Hiroyuki Hanzawa, Kengo Watanabe, Satoshi Yoda, Noriko Yanagitani, Aaron N Hata, Alice T Shaw, Makoto Nishio, Naoya Fujita, Takeshi Isoyama
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 3604 (08 09 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31399568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Benzamides
• Indazoles
• Lactams
• Lactams, Macrocyclic
• Membrane Glycoproteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pyrazoles
• Crizotinib
• Protein-Tyrosine Kinases
• ROS1 protein, human
• Receptor, trkB
• entrectinib
• lorlatinib

Topics

• Aminopyridines
• Benzamides (pharmacology)
• Carcinoma, Non-Small-Cell Lung (genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Crizotinib (pharmacology)
• Drug Development
• Drug Resistance, Neoplasm (drug effects, genetics)
• Humans
• Indazoles (pharmacology)
• Lactams
• Lactams, Macrocyclic (pharmacology)
• Lung Neoplasms (genetics)
• Membrane Glycoproteins (antagonists & inhibitors)
• Mutation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics)
• Pyrazoles
• Receptor, trkB (antagonists & inhibitors)