Preclinical characterization and antitumor efficacy of DS-6051b, a novel, orally available small molecule tyrosine kinase inhibitor of ROS1 and NTRKs

Personalized therapy for lung cancer: Striking a moving target

“…However, entrectinib does not appear to be effective against G2032R in preclinical models and might be ineffective in patients that have received prior therapy with crizotinib; to the contrary, lorlatinib has shown promising activity in the acquired resistance setting for patients with ROS1-positive NSCLC. Several other promising agents are also under investigation (77)(78)(79)(80)(81)(82)(83). As TKIs are being employed in the treatment of other oncogenic drivers such as cabozantinib or vandetanib for RET and entrectinib for NTRK, the emergent resistance mutations are beginning to be reported in the literature.…”

Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study

“…Drugs targeting fusion kinases are an emerging paradigm in the management of these cancers. DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for ROS1, NTRK1, NTRK2, and NTRK3 receptors and suppression of their activity in vitro [ 20 ]. DS-6051b also has antitumor activity in glioblastoma cell lines harboring a ROS1 fusion, and in human colorectal cancer cell lines harboring a NTRK1 fusion [ 20 ].…”

“…DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for ROS1, NTRK1, NTRK2, and NTRK3 receptors and suppression of their activity in vitro [ 20 ]. DS-6051b also has antitumor activity in glioblastoma cell lines harboring a ROS1 fusion, and in human colorectal cancer cell lines harboring a NTRK1 fusion [ 20 ]. An in vivo antitumor effect has been demonstrated in a mouse model grafted with the respective tumor cell lines [ 20 ].…”

“…DS-6051b also has antitumor activity in glioblastoma cell lines harboring a ROS1 fusion, and in human colorectal cancer cell lines harboring a NTRK1 fusion [ 20 ]. An in vivo antitumor effect has been demonstrated in a mouse model grafted with the respective tumor cell lines [ 20 ]. DS-6051b inhibits the intracellular phosphorylation of ROS1 and NTRK1 in a concentration-dependent manner.…”

“…It also inhibits the growth of ROS1 - and NTRK1 -fusion tumor xenografts in a dose-dependent manner without causing severe body weight loss. A major advantage of DS-6051b over other compounds is that it is also effective against crizotinib-resistant ROS1 mutations and inhibits the growth of Ba/F3 cells expressing NTRK gene rearrangements, both in vitro and in vivo [ 20 ]. In addition to DS-6051b, other drugs in development for cancer treatment include larotrectinib (LOXO101), an NTRK inhibitor, and entrectinib (RXDX101), an NTRK/ROS1 inhibitor.…”