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ROS1 – Gene, Mutation & Targeted Therapy

ROS1 is a gene whose alterations occur in certain cancers such as non-small cell lung cancer, enabling targeted therapy approaches.

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Things worth knowing about "ROS1"

ROS1 is a gene whose alterations occur in certain cancers such as non-small cell lung cancer, enabling targeted therapy approaches.

What is ROS1?

ROS1 (proto-oncogene tyrosine kinase ROS1) is a gene that provides the blueprint for an enzyme called a receptor tyrosine kinase. This enzyme plays a key role in regulating cell growth, division, and survival. Under normal conditions, ROS1 is involved in the development and function of various tissues. However, when specific genetic alterations – known as ROS1 rearrangements or ROS1 fusions – occur, the enzyme can become permanently activated, promoting uncontrolled cell growth and potentially leading to cancer.

Clinical Significance

ROS1 rearrangements have been identified in several cancer types, most commonly in non-small cell lung cancer (NSCLC), where they occur in approximately 1–2% of all cases. Affected patients are often younger, non-smokers or light smokers, and frequently have adenocarcinoma histology. ROS1 alterations have also been described in other tumor types, including:

Cholangiocarcinoma (bile duct cancer)
Gastric cancer
Ovarian cancer
Colorectal cancer
Glioblastoma

Molecular Mechanism

In a ROS1 rearrangement, a segment of the chromosome carrying the ROS1 gene breaks off and joins with another gene. The resulting fusion protein is permanently active and continuously sends growth signals to the cell, bypassing normal regulatory mechanisms. This process, known as oncogenic activation, is a key driver of tumor growth in affected patients.

Diagnosis

Detection of a ROS1 alteration is performed through molecular pathology testing of tumor tissue. Common methods include:

Fluorescence in situ hybridization (FISH): The gold standard for detecting gene rearrangements
Immunohistochemistry (IHC): A screening method to detect ROS1 protein expression
Next-generation sequencing (NGS): Comprehensive genomic profiling that can simultaneously detect multiple alterations
Reverse transcriptase PCR (RT-PCR): Detection of specific fusion transcripts

Testing for ROS1 is part of routine molecular pathology workup in patients with advanced NSCLC and is recommended by international clinical guidelines.

Targeted Therapy

Patients with ROS1-positive tumors may benefit from tyrosine kinase inhibitors (TKIs), which selectively block the aberrant ROS1 fusion protein. Approved agents include:

Crizotinib: The first approved TKI for ROS1-positive NSCLC; also inhibits ALK and MET
Entrectinib: A newer TKI with additional activity against NTRK fusions and efficacy against brain metastases
Lorlatinib: A third-generation TKI with broad activity and efficacy against resistance mutations
Repotrectinib: The most recently approved TKI, effective in pretreated patients with resistance mutations

Compared to conventional chemotherapy, these targeted therapies show significantly higher response rates and better tolerability in ROS1-positive tumors.

Resistance Mechanisms

As with other targeted therapies, resistance can develop over the course of treatment. Common mechanisms include:

Acquisition of secondary mutations in the ROS1 kinase domain (e.g., the G2032R mutation)
Activation of bypass signaling pathways (e.g., via KRAS, EGFR, or MET)
Epithelial-to-mesenchymal transition

In the event of treatment failure, a repeat biopsy and molecular analysis are recommended to identify the resistance mechanism and guide subsequent therapy decisions.

References

Shaw AT et al. - Crizotinib in ROS1-rearranged non-small-cell lung cancer. New England Journal of Medicine, 2014; 371(21):1963–1971.
Drilon A et al. - Entrectinib in ROS1 fusion-positive non-small-cell lung cancer. Journal of Clinical Oncology, 2020; 38(25):2970–2979.
European Medicines Agency (EMA) - Product information for Crizotinib, Entrectinib, and Repotrectinib. Available at: www.ema.europa.eu

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