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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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Showing 1 to 9 of 9 entries

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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	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	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
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	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	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.

Showing 1 to 9 of 9 entries

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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 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	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 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 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 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 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	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	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 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

Showing 1 to 14 of 14 entries

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