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Ref Type Journal Article
PMID (37587872)
Authors Iyer SR, Nusser K, Jones K, Shinde P, Keddy C, Beach CZ, Aguero E, Force J, Shinde U, Davare MA
Title Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors.
Journal Vol Issue Date Pages Journal Short Title
EMBO molecular medicine 2023 Aug 17 e17367 EMBO Mol Med
URL
Abstract Text ROS1 is the largest receptor tyrosine kinase in the human genome. Rearrangements of the ROS1 gene result in oncogenic ROS1 kinase fusion proteins that are currently the only validated biomarkers for targeted therapy with ROS1 TKIs in patients. While numerous somatic missense mutations in ROS1 exist in the cancer genome, their impact on catalytic activity and pathogenic potential is unknown. We interrogated the AACR Genie database and identified 34 missense mutations in the ROS1 tyrosine kinase domain for further analysis. Our experiments revealed that these mutations have varying effects on ROS1 kinase function, ranging from complete loss to significantly increased catalytic activity. Notably, Asn and Gly substitutions at Asp2113 in the ROS1 kinase domain were found to be TKI-sensitive oncogenic variants in cell-based model systems. In vivo experiments showed that ROS1 D2113N induced tumor formation that was sensitive to crizotinib and lorlatinib, FDA-approved ROS1-TKIs. Collectively, these findings highlight the tumorigenic potential of specific point mutations within the ROS1 kinase domain and their potential as therapeutic targets with FDA-approved ROS1-TKIs.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ROS1 D2113E missense no effect - predicted ROS1 D2113E lies within the protein kinase domain of the Ros1 protein (UniProt.org). D2113E results in similar kinase activity to wild-type Ros1 in culture (PMID: 37587872), and therefore, is predicted to have no effect on Ros1 protein function.
ROS1 D2113G missense gain of function ROS1 D2113G lies within the protein kinase domain of the Ros1 protein (UniProt.org). D2113G results in increased Ros1 activity, phosphorylation of Shp2 and Stat3, and colony formation in culture (PMID: 37587872) and has been demonstrated to confer resistance to ROS1 tyrosine kinase inhibitors in the context of ROS1 fusions in culture (PMID: 26372962). Y
ROS1 D2113N missense gain of function ROS1 D2113N lies within the protein kinase domain of the Ros1 protein (UniProt.org). D2113N results in increased Ros1 activity, phosphorylation of Shp2 and Stat3, and colony formation in culture, and induces tumor formation in a mouse model (PMID: 37587872), and has been demonstrated to enhance resistance to ROS1 tyrosine kinase inhibitors with concurrent ROS1 G2032R in the context of a ROS1 fusion in culture (PMID: 26372962). Y
ROS1 D2113Y missense loss of function - predicted ROS1 D2113Y lies within the protein kinase domain of the Ros1 protein (UniProt.org). D2113Y results in decreased Ros1 phosphorylation in culture (PMID: 37587872), and therefore, is predicted to lead to a loss of Ros1 protein function.
ROS1 E2071K missense gain of function - predicted ROS1 E2071K lies within the protein kinase domain of the Ros1 protein (UniProt.org). E2071K results in increased colony formation and tumor formation that is not statistically significant relative to wild-type Ros1 and increased Ros1 phosphorylation in culture (PMID: 37587872), and therefore, is predicted to lead to a gain of Ros1 protein function.
ROS1 I2151F missense gain of function - predicted ROS1 I2151F lies within the protein kinase domain of the Ros1 protein (UniProt.org). I2151F results in similar colony formation to wild-type Ros1 but increased Ros1 phosphorylation in culture (PMID: 37587872), and therefore, is predicted to lead to a gain of Ros1 protein function.
ROS1 K1980E missense loss of function ROS1 K1980E lies within the protein kinase domain of the Ros1 protein (UniProt.org). K1980E results in loss of Ros1 protein function as demonstrated by decreased Ros1 phosphorylation, and failure to induce colony growth in culture or tumor formation in a mouse model (PMID: 37587872).
ROS1 L1949F missense gain of function - predicted ROS1 L1949F lies within the protein kinase domain of the Ros1 protein (UniProt.org). L1949F results in increased colony formation that is not statistically significant relative to wild-type Ros1 and increased Ros1 phosphorylation in culture (PMID: 37587872), and therefore, is predicted to lead to a gain of Ros1 protein function.
ROS1 S1986F missense gain of function - predicted ROS1 S1986F lies within the protein kinase domain of the Ros1 protein (UniProt.org). S1986F results in increased colony formation that is not statistically significant relative to wild-type Ros1 and increased Ros1 phosphorylation in culture (PMID: 37587872), and has been demonstrated to occur as a secondary drug resistance mutation and increase cell migration and invasion in the context of ROS1 fusions in culture (PMID: 36265718, PMID: 27401242, PMID: 32776005), and therefore, is predicted to lead to a gain of Ros1 protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ROS1 D2113G Advanced Solid Tumor sensitive Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, Augtyro (repotrectinib) inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited proliferation of transformed cells expressing ROS1 D2113N in culture and inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited proliferation of transformed cells expressing ROS1 D2113N in culture (PMID: 37587872). 37587872
ROS1 D2113G Advanced Solid Tumor sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113G Advanced Solid Tumor sensitive Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive NUV-520 Preclinical - Cell culture Actionable In a preclinical study, NUV-520 inhibited proliferation of transformed cells expressing ROS1 D2113N in culture (PMID: 37587872). 37587872
ROS1 D2113G Advanced Solid Tumor sensitive TNO155 Preclinical - Cell culture Actionable In a preclinical study, TNO155 inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113G Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell culture Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113G Advanced Solid Tumor sensitive NUV-520 Preclinical - Cell culture Actionable In a preclinical study, NUV-520 inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive RMC-4550 Preclinical - Cell culture Actionable In a preclinical study, RMC-4550 inhibited proliferation of transformed cells expressing ROS1 D2113N in culture (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive Crizotinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xalkori (crizotinib) inhibited proliferation of transformed cells expressing ROS1 D2113N in culture and inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 37587872). 37587872
ROS1 D2113G Advanced Solid Tumor sensitive Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) inhibited proliferation of transformed cells expressing ROS1 D2113G in culture (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive TNO155 Preclinical - Cell culture Actionable In a preclinical study, TNO155 inhibited proliferation of transformed cells expressing ROS1 D2113N in culture (PMID: 37587872). 37587872
ROS1 D2113N Advanced Solid Tumor sensitive Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, Augtyro (repotrectinib) inhibited proliferation of transformed cells expressing ROS1 D2113N in culture (PMID: 37587872). 37587872