ROS1

ROS1 (c-ros oncogene 1), also known as proto-oncogene c-Ros or mcf3, is a protein that in humans is encoded by the ROS1 gene. It is a member of the insulin receptor family of tyrosine kinase receptors and is involved in the regulation of cell growth, differentiation, and survival. ROS1 has been identified as a driver mutation in a variety of cancers, including non-small cell lung cancer (NSCLC), glioblastoma, and cholangiocarcinoma.

Function

ROS1 is a receptor tyrosine kinase (RTK) that plays a critical role in the development and differentiation of several tissues. Upon binding of its ligands, which are yet to be fully identified, ROS1 undergoes autophosphorylation and activates various downstream signaling pathways, including the PI3K/AKT/mTOR pathway, the RAS/RAF/MEK/ERK pathway, and the STAT3 pathway. These pathways are involved in cellular processes such as proliferation, survival, and motility.

Genetic Alterations and Cancer

Alterations in the ROS1 gene, including point mutations, amplifications, and especially chromosomal rearrangements, have been implicated in the pathogenesis of several types of cancer. The most common alteration is a gene fusion, where the ROS1 gene fuses with another gene, leading to the expression of a constitutively active chimeric ROS1 protein kinase. This constitutive kinase activity can drive oncogenesis by activating downstream signaling pathways independent of ligand binding.

In NSCLC, the ROS1 gene can fuse with various partners, such as CD74, SLC34A2, SDC4, EZR, LRIG3, and FIG. These fusions are present in approximately 1-2% of NSCLC cases and are more frequently observed in younger patients, non-smokers, and those with adenocarcinoma histology.

Diagnosis and Treatment

The presence of ROS1 fusions in tumors can be detected using techniques such as fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS). Identifying ROS1 fusions is crucial for the management of patients with NSCLC, as they are predictive biomarkers for the efficacy of ROS1 inhibitors.

Several tyrosine kinase inhibitors (TKIs) have shown activity against ROS1-positive tumors. Crizotinib, a multi-targeted TKI, was the first drug approved for the treatment of ROS1-positive NSCLC. Other ROS1 inhibitors, such as ceritinib, lorlatinib, and entrectinib, have also demonstrated efficacy in treating ROS1-positive cancers.

Research and Future Directions

Research is ongoing to better understand the biology of ROS1 in cancer and to develop more effective therapies for patients with ROS1-positive tumors. This includes the development of next-generation ROS1 inhibitors that can overcome resistance to current treatments, as well as combination therapies that target multiple pathways involved in tumor growth and survival.

See Also

• Tyrosine kinase inhibitor
• Non-small cell lung cancer
• Gene fusion
• Oncogene