ROS1-positive non-small cell lung cancer (NSCLC): biology, diagnostics, therapeutics and resistance

Abstract

ROS1 is a proto-oncogene encoding a receptor tyrosine protein kinase (RTK), homologous to the v – Ros sequence of University of Manchester tumours virus 2 (UR2) sarcoma virus, whose ligands are still being investigated. ROS1 fusion genes have been identified in various types of tumours. As an oncoprotein, it promotes cell proliferation, activation and cell cycle progression by activating downstream signalling pathways, accelerating the development and progression of non-small cell lung cancer (NSCLC). Studies have demonstrated that ROS1 inhibitors are effective in patients with ROS1-positive NSCLC and are used for first-line clinical treatment. These small molecule inhibitors provide a rational therapeutic option for the treatment of ROS1-positive patients. Inevitably, ROS1 inhibitor resistance mutations occur, leading to tumours recurrence or progression. Here, we comprehensively review the identified biological properties and Differential subcellular localisation of ROS1 fusion oncoprotein promotes tumours progression. We summarise recently completed and ongoing clinical trials of the classic and new ROS1 inhibitors. More importantly, we classify the complex evolving tumours cell resistance mechanisms. This review contributes to our understanding of the biological properties of ROS1 and current therapeutic advances and resistant tumours cells, and the future directions to develop ROS1 inhibitors with durable effects.

Keywords:

• Non-small cell lung cancer
• ROS1-positive
• diagnostics
• drug resistance
• targeted therapies

Author contributions

ZQY, JC, XCP and ZQC contributed to this review with the design. ZQY, MW, WZ, and NL reviewed the references. ZQY, JC, XCP and ZQC wrote the manuscript. ZQY, MXM, YYC and MW designed and produced the tables and figures. JC and XCP acquired the funding. All authors read and approved the manuscript for publication.

Disclosure statement

The authors declare that they have no competing interests.

Data availability statement

All information provided in this review is documented by relevant references.

Additional information

Funding

This study was supported by Hubei Province Health and Family Planning Scientific Research Project [grant nos. WJ2015MB212 and WJ2018H201] to JC, and the National Innovation and Entrepreneurship Training Program for College Students [grant no. 202010489017] to XCP.