ROS1

Official Full Name

ROS proto-oncogene 1, receptor tyrosine kinase

Organism

Homo sapiens

GeneID

6098

Background

This proto-oncogene, highly-expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. [provided by RefSeq, Jul 2008]

Synonyms

ROS; MCF3; c-ros-1;

Bio Chemical Class

Kinase

Protein Sequence

MKNIYCLIPKLVNFATLGCLWISVVQCTVLNSCLKSCVTNLGQQLDLGTPHNLSEPCIQGCHFWNSVDQKNCALKCRESCEVGCSSAEGAYEEEVLENADLPTAPFASSIGSHNMTLRWKSANFSGVKYIIQWKYAQLLGSWTYTKTVSRPSYVVKPLHPFTEYIFRVVWIFTAQLQLYSPPSPSYRTHPHGVPETAPLIRNIESSSPDTVEVSWDPPQFPGGPILGYNLRLISKNQKLDAGTQRTSFQFYSTLPNTIYRFSIAAVNEVGEGPEAESSITTSSSAVQQEEQWLFLSRKTSLRKRSLKHLVDEAHCLRLDAIYHNITGISVDVHQQIVYFSEGTLIWAKKAANMSDVSDLRIFYRGSGLISSISIDWLYQRMYFIMDELVCVCDLENCSNIEEITPPSISAPQKIVADSYNGYVFYLLRDGIYRADLPVPSGRCAEAVRIVESCTLKDFAIKPQAKRIIYFNDTAQVFMSTFLDGSASHLILPRIPFADVKSFACENNDFLVTDGKVIFQQDALSFNEFIVGCDLSHIEEFGFGNLVIFGSSSQLHPLPGRPQELSVLFGSHQALVQWKPPALAIGANVILISDIIELFELGPSAWQNWTYEVKVSTQDPPEVTHIFLNISGTMLNVPELQSAMKYKVSVRASSPKRPGPWSEPSVGTTLVPASEPPFIMAVKEDGLWSKPLNSFGPGEFLSSDIGNVSDMDWYNNSLYYSDTKGDVFVWLLNGTDISENYHLPSIAGAGALAFEWLGHFLYWAGKTYVIQRQSVLTGHTDIVTHVKLLVNDMVVDSVGGYLYWTTLYSVESTRLNGESSLVLQTQPWFSGKKVIALTLDLSDGLLYWLVQDSQCIHLYTAVLRGQSTGDTTITEFAAWSTSEISQNALMYYSGRLFWINGFRIITTQEIGQKTSVSVLEPARFNQFTIIQTSLKPLPGNFSFTPKVIPDSVQESSFRIEGNASSFQILWNGPPAVDWGVVFYSVEFSAHSKFLASEQHSLPVFTVEGLEPYALFNLSVTPYTYWGKGPKTSLSLRAPETVPSAPENPRIFILPSGKCCNKNEVVVEFRWNKPKHENGVLTKFEIFYNISNQSITNKTCEDWIAVNVTPSVMSFQLEGMSPRCFIAFQVRAFTSKGPGPYADVVKSTTSEINPFPHLITLLGNKIVFLDMDQNQVVWTFSAERVISAVCYTADNEMGYYAEGDSLFLLHLHNRSSSELFQDSLVFDITVITIDWISRHLYFALKESQNGMQVFDVDLEHKVKYPREVKIHNRNSTIISFSVYPLLSRLYWTEVSNFGYQMFYYSIISHTLHRILQPTATNQQNKRNQCSCNVTEFELSGAMAIDTSNLEKPLIYFAKAQEIWAMDLEGCQCWRVITVPAMLAGKTLVSLTVDGDLIYWIITAKDSTQIYQAKKGNGAIVSQVKALRSRHILAYSSVMQPFPDKAFLSLASDTVEPTILNATNTSLTIRLPLAKTNLTWYGITSPTPTYLVYYAEVNDRKNSSDLKYRILEFQDSIALIEDLQPFSTYMIQIAVKNYYSDPLEHLPPGKEIWGKTKNGVPEAVQLINTTVRSDTSLIISWRESHKPNGPKESVRYQLAISHLALIPETPLRQSEFPNGRLTLLVTRLSGGNIYVLKVLACHSEEMWCTESHPVTVEMFNTPEKPYSLVPENTSLQFNWKAPLNVNLIRFWVELQKWKYNEFYHVKTSCSQGPAYVCNITNLQPYTSYNVRVVVVYKTGENSTSLPESFKTKAGVPNKPGIPKLLEGSKNSIQWEKAEDNGCRITYYILEIRKSTSNNLQNQNLRWKMTFNGSCSSVCTWKSKNLKGIFQFRVVAANNLGFGEYSGISENIILVGDDFWIPETSFILTIIVGIFLVVTIPLTFVWHRRLKNQKSAKEGVTVLINEDKELAELRGLAAGVGLANACYAIHTLPTQEEIENLPAFPREKLTLRLLLGSGAFGEVYEGTAVDILGVGSGEIKVAVKTLKKGSTDQEKIEFLKEAHLMSKFNHPNILKQLGVCLLNEPQYIILELMEGGDLLTYLRKARMATFYGPLLTLVDLVDLCVDISKGCVYLERMHFIHRDLAARNCLVSVKDYTSPRIVKIGDFGLARDIYKNDYYRKRGEGLLPVRWMAPESLMDGIFTTQSDVWSFGILIWEILTLGHQPYPAHSNLDVLNYVQTGGRLEPPRNCPDDLWNLMTQCWAQEPDQRPTFHRIQDQLQLFRNFFLNSIYKSRDEANNSGVINESFEGEDGDVICLNSDDIMPVALMETKNREGLNYMVLATECGQGEEKSEGPLGSQESESCGLRKEEKEPHADKDFCQEKQVAYCPSGKPEGLNYACLTHSGYGDGSD

Open

Disease

Adrenal cancer, Breast cancer, Colorectal cancer, Lung cancer, Metastatic tumour, Non-small-cell lung cancer, Solid tumour/cancer

Approved Drug

4 +

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

ROS1, also known as c-ros proto-oncogene receptor tyrosine kinase, was first identified in 1982 within the UR2 avian sarcoma virus as a viral proto-oncogene with unique oncogenic potential. ROS1 belongs to the insulin receptor family, but its precise biological functions in humans remain incompletely understood. The ROS1 gene is located on human chromosome 6q21 and consists of three main regions: an intracellular tyrosine kinase domain, an extracellular domain, and a transmembrane region. When ROS1 undergoes gene rearrangements, the extracellular region is typically lost while the transmembrane and intracellular kinase regions are retained, with exons 32–36 being the most common sites for such rearrangements.

Figure 1. Diagram of ROS1 gene structure and signaling. (Drilon A, et al., 2021)

ROS1 Signaling Pathways

The ROS1 protein is composed of an intracellular kinase domain, a transmembrane region, and an extracellular domain. Acting as a critical cell surface receptor, ROS1 engages specific ligands via its extracellular domain, triggering activation of its intracellular kinase domain through the transmembrane region. Activation of ROS1 leads to autophosphorylation of specific intracellular tyrosine residues, which in turn recruit SH2-domain-containing and other adaptor proteins to propagate downstream signaling. Key pathways influenced by ROS1 include RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, and JAK-STAT3, broadly regulating cell survival, growth, and proliferation. Non-receptor protein tyrosine phosphatases SHP1 and SHP2 also interact with ROS1, serving as important downstream effectors. SHP2, a multifunctional signaling protein, may act as a critical mediator of ROS1 signaling during normal development, tissue homeostasis, and tumorigenesis, whereas SHP1 dephosphorylates ROS1, dampening receptor tyrosine kinase-mediated signaling.

ROS1 in Cancer

ROS1 was first identified in non-small cell lung cancer (NSCLC) in 2007 and has since been detected in other malignancies, including colorectal and ovarian cancers. In NSCLC, ROS1 often undergoes gene fusions with partners such as SLC34A and CD74, leading to constitutive activation of downstream signaling pathways and tumorigenesis. The clinical detection rate of ROS1 gene fusions in NSCLC patients is approximately 1–2%, most commonly observed in younger, non-smoking or light-smoking patients with lung adenocarcinoma, and predominantly in females. ROS1 fusions rarely co-occur with other major lung cancer driver mutations, such as EGFR, KRAS, or ALK fusions; in adenocarcinoma patients lacking these mutations, ROS1 fusion positivity can reach up to 11%.

Due to structural similarity between ROS1 and ALK kinase domains, ALK inhibitors (excluding alectinib) have demonstrated efficacy in controlling disease in ROS1-rearranged patients. Currently, several targeted therapies, including crizotinib, ceritinib, brigatinib, lorlatinib, and entrectinib, are available for ROS1 fusion-positive NSCLC. Among these, repotrectinib (TPX-0005, a second-generation ALK/ROS1/NTRK inhibitor) and taletrectinib (AB-106, a second-generation ROS1/NTRK inhibitor) have shown notable efficacy in treatment-naïve ROS1-positive NSCLC patients, achieving objective response rates up to 93%, while also demonstrating promising results in resistant cases. With ongoing clinical advancements in ROS1-targeted therapeutics, patients harboring ROS1 fusions are expected to have increasingly effective treatment options in the near future.

Reference

Drilon A, Jenkins C, Iyer S, et al. ROS1-dependent cancers - biology, diagnostics and therapeutics. Nat Rev Clin Oncol. 2021 Jan;18(1):35-55.
Boulanger MC, Schneider JL, Lin JJ. Advances and future directions in ROS1 fusion-positive lung cancer. Oncologist. 2024 Nov 4;29(11):943-956.

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