Resistance mechanisms and potent-targeted therapies of ROS1-positive lung cancer

The discovery of targetable mutations, which cause gene rearrangement, led to a major advancement in the treatment of patients with non-small cell lung cancer (NSCLC), and cancers with such mutations can be paired with drugs which specifically target them. c-ros oncogene (ROS1) positive NSCLC is one molecular subtype of NSCLC with a therapeutic target. Currently, different targeted therapies and ROS1 inhibitors have been discovered, but all are in different investigational phases, with only one (crizotinib) which is FDA approved. Crizotinib is a small-molecule tyrosine kinase inhibitor (TKI) which was discovered to actively inhibit ALK, MET, and ROS1. Crizotinib has shown to be remarkably efficacious against ROS1 lung cancer, prompting ROS1 detection in lung cancer to be quite significant. Sadly, crizotinib resistance in ROS1 is a frequent occurrence which poses a major clinical challenge in the successful treatment of ROS1 lung cancer; hence, the discovery of the second and third generation ROS1 inhibitors is of utmost importance. In this review, we discuss the underlying mechanisms through which ROS1 tumor cells acquire resistance to crizotinib-the first-line drug for ROS1-positive NSCLC, and summarize various new potent drugs which can overcome this resistance and serve as viable alternatives.