Cellular environment showing ROS1 proteins in endosomes and endoplasmic reticulum.

ROS1 holds the key to cancer treatment?

Samir D’Costa in Health & Wellness December 2025 • 4 min read.

"A breakthrough study illuminates how the subcellular location of ROS1 fusion proteins can dictate oncogenic signaling, opening new avenues for targeted therapies."

Cancer is often driven by the aberrant hyper-activation of receptor tyrosine kinases (RTKs), which are crucial for cell growth and differentiation. This activation results from various genetic alterations, including gene rearrangements that lead to the formation of fusion proteins. Among these, fusions involving the anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) have gained significant attention.

In these fusions, the kinase domain of the RTK is joined in cis to various N-terminal partners. Kinase inhibitors (TKIs) like crizotinib have proven effective in treating cancers driven by these fusions; however, resistance remains a significant challenge, highlighting the need for a deeper understanding of their oncogenic mechanisms.

A crucial aspect of these oncoprotein kinase fusions is how their subcellular localization influences their oncogenic properties. Many oncoprotein fusion kinases, such as ALK and ROS1 variants, acquire subcellular localization signals from their N-terminal partners. This raises the question of whether abnormal subcellular localization significantly contributes to their ability to promote cancer.

How Does Subcellular Localization Regulate Oncogenic Signaling?

Cellular environment showing ROS1 proteins in endosomes and endoplasmic reticulum.

Researchers investigated the differential functional properties of various ROS1 oncoprotein fusions. They engineered a genetically controlled system to express common ROS1 fusion oncoproteins found in patient tumors, including CD74-ROS1, SDC4-ROS1, and SLC34A2-ROS1. A topological analysis indicated that these fusions result in a membrane-anchored, cytoplasmic-facing kinase domain. All three ROS1 fusions showed constitutive kinase activation, as measured by ROS1 phosphorylation.

The ability of ROS1 fusions to activate the RAS/MAPK pathway varied significantly. SDC4-ROS1 and SLC34A2-ROS1 activated the MAPK pathway, while CD74-ROS1 did not substantially induce RAS/MAPK pathway signaling. These findings were confirmed in patient-derived NSCLC models, where knockdown of SDC4-ROS1 and SLC34A2-ROS1 suppressed the MAPK pathway, but silencing CD74-ROS1 did not.

SDC4-ROS1 and SLC34A2-ROS1: Fusion oncoproteins localized to endosomes, activating the MAPK pathway.
CD74-ROS1: Variants localized to the endoplasmic reticulum (ER), showing compromised activation of MAPK.
FYVE-CD74-ROS1: Re-localization of CD74-ROS1 from the ER to endosomes restored MAPK signaling.

An emerging mechanism involves the protein phosphatase SHP2 (PTPN11), which enhances RAS-GTP levels and RAF-MEK-ERK activation. SHP2 inhibition was highly effective in NSCLC cell lines where the MAPK pathway operated downstream of the ROS1 fusion but less effective when the MAPK pathway was disconnected from the ROS1 fusion. Mutation of tyrosine phosphorylation sites within SDC4-ROS1 abrogated SHP-2 binding, indicating a direct interaction. This suggests that MAPK pathway activation is necessary and sufficient for cell survival in cells harboring SDC4-ROS1 and SLC34A2-ROS1 fusions, but not in those with CD74-ROS1.

What Does This Mean for Future Cancer Treatments?

These findings demonstrate that the specific N-terminal fusion partners in gene rearrangements involving RTKs can directly control MAPK signaling by influencing subcellular localization. Understanding the subcellular localization of aberrant gene fusion oncoproteins could provide additional avenues for cancer treatment. Targeting these specific localizations may offer more effective and personalized therapeutic strategies, especially in overcoming resistance to existing treatments like crizotinib. Further research into how subcellular localization regulates fusion oncoprotein activity could lead to new biomarkers and therapeutic targets, improving outcomes for cancer patients.

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This article is based on research published under:

DOI-LINK: 10.1158/0008-5472.can-18-1492, Alternate LINK

Title: Differential Subcellular Localization Regulates Oncogenic Signaling By Ros1 Kinase Fusion Proteins

Subject: Cancer Research

Journal: Cancer Research

Publisher: American Association for Cancer Research (AACR)

Authors: Dana S. Neel, David V. Allegakoen, Victor Olivas, Manasi K. Mayekar, Golzar Hemmati, Nilanjana Chatterjee, Collin M. Blakely, Caroline E. Mccoach, Julia K. Rotow, Anh Le, Niki Karachaliou, Rafael Rosell, Jonathan W. Riess, Robert Nichols, Robert C. Doebele, Trever G. Bivona

Published: 2018-12-11

Everything You Need To Know

What is ROS1, and why is it important in cancer treatment?

ROS1 is a proto-oncogene that encodes a receptor tyrosine kinase (RTK). In the context of cancer, ROS1 can become part of a fusion protein due to genetic rearrangements. These fusions often lead to constitutive kinase activation, driving uncontrolled cell growth. Understanding ROS1 fusions is vital because they can be targeted with kinase inhibitors like crizotinib, offering a therapeutic avenue for cancers driven by these specific genetic alterations. However, resistance to these inhibitors is a challenge, necessitating a deeper understanding of their mechanisms.

What does 'subcellular localization' mean, and why does it matter for ROS1 fusion proteins?

Subcellular localization refers to where a protein resides within a cell, such as the endosomes or endoplasmic reticulum (ER). It is crucial because the location of ROS1 fusion proteins can significantly influence their oncogenic properties. For instance, SDC4-ROS1 and SLC34A2-ROS1 localize to endosomes and activate the MAPK pathway, while CD74-ROS1 localizes to the ER and shows compromised MAPK activation. This differential localization can determine the effectiveness of targeted therapies.

What is the RAS/MAPK pathway, and how does it relate to ROS1 fusions?

The RAS/MAPK pathway is a signaling cascade vital for cell growth and differentiation. In the context of ROS1 fusions, its activation level can vary depending on the specific fusion and its subcellular localization. For example, SDC4-ROS1 and SLC34A2-ROS1 fusions effectively activate the MAPK pathway, making cells harboring these fusions more dependent on this pathway for survival. Conversely, CD74-ROS1 shows compromised activation of the MAPK pathway, influencing the response to SHP2 inhibition.

What are kinase inhibitors, and why are they relevant to ROS1-driven cancers?

Kinase inhibitors, such as crizotinib, are drugs designed to block the activity of kinases, like ROS1, that are driving cancer growth. They have shown effectiveness in treating cancers driven by ALK and ROS1 fusions. However, resistance to these inhibitors remains a significant clinical challenge. A deeper understanding of the oncogenic mechanisms, influenced by subcellular localization, could help in developing more effective, personalized treatment strategies and overcoming resistance.

What is SHP2, and what role does it play in ROS1 fusion signaling?

SHP2 (PTPN11) is a protein phosphatase that enhances RAS-GTP levels and RAF-MEK-ERK activation within the MAPK pathway. Its role is significant because it can amplify MAPK signaling downstream of ROS1 fusions. Inhibiting SHP2 is highly effective in non-small cell lung cancer (NSCLC) cell lines where the MAPK pathway operates downstream of the ROS1 fusion, but less effective when the MAPK pathway is disconnected from the ROS1 fusion. This highlights the importance of SHP2 in specific oncogenic contexts.